TW201836642A - Methods of treating autoimmune and inflammatory diseases - Google Patents

Abstract

Provided herein are biomarkers and therapies for the treatment of autoimmune and/or inflammatory diseases, such as lupus, and methods of using BTK inhibitors. In particular, provided are biomarkers for patient selection and prognosis in lupus, as well as methods of therapeutic treatment, articles of manufacture and methods for making them, diagnostic kits, methods of detection and methods of advertising related thereto.

Description

Methods for treating autoimmune and inflammatory diseases

Provided herein are biomarkers and therapies for treating autoimmune and inflammatory diseases, as well as methods of using BTK inhibitors. In particular, it provides methods for selecting patients with autoimmune and inflammatory diseases and prognosis, as well as medical treatment methods, products and manufacturing methods, diagnostic kits, detection methods, and related promotion methods.

Autoimmune and inflammatory diseases and conditions remain a significant threat to human health. Despite significant advances in treating autoimmune and inflammatory diseases and conditions, improved therapies are still sought. Many autoimmune and inflammatory diseases show signs of heterogeneity. For example, systemic lupus erythematosus (SLE) is a disease that shows signs of heterogeneity in a population of SLE patients. See Kennedy et al., Lupus Sci. & Med., 2015; 2: e000080. In view of this heterogeneity, in addition to new methods for treating autoimmune and inflammatory diseases (e.g., SLE), there is a need for a method to identify certain patients using diagnostic biomarkers that can improve treatment outcomes. Plasmablasts are fast-dividing, short-lived antibody-secreting cells. Increases in plasmablasts have been identified in the blood of juvenile lupus patients, and overall increase the abundance of antibody transcripts in lupus patients. E. Arce et al., J. Immunol. 167 , 2361-2369 (2001); L, Bennett et al., J. Exp. Med. 197 , 711-723 (2003). Although plasmablasts represent a small percentage of B cells in the blood, they are responsible for most antibody transcripts found in whole blood mRNAs. Protein kinases are the largest family of human enzymes, covering far more than 500 proteins. Bruton's Tyrosine Kinase (BTK) is a member of the Tec family of tyrosine kinases and is a regulator of early B cell development and mature B cell activation, signaling, and survival. Signs of the role of BTK in allergic and / or autoimmune and / or inflammatory diseases have been identified in BTK-deficient mouse models. For example, in a standard preclinical murine SLE model, BTK defects have been shown to significantly slow disease progression. In addition, BTK-deficient mice are also resistant to collagen-induced arthritis and may be less susceptible to Staphylococcus-induced arthritis. Substantial evidence supports the role of B cells and the humoral immune system in the pathogenesis of autoimmune and / or inflammatory diseases. See, for example, WO 2012/118750. Protein-based therapeutics that develop to deplete B cells, such as Rituxan, represent a method of treating a variety of autoimmune and / or inflammatory diseases. Because of the role of BTK in B cell activation, BTK inhibitors are suitable as inhibitors of B cell-mediated pathogenic activities, such as autoantibody production. BTK has also been shown in osteoclasts, mast cells and monocytes and has been shown to be important for the function of these cells. For example, BTK deficiency in mice is associated with impaired IgE-mediated mast cell activation (significantly reduced release of TNF-α and other inflammatory interleukins), and BTK deficiency in humans is associated with activated monocytes. TNF-α production is significantly reduced. Inhibition of BTK activity is suitable for the treatment of allergic conditions and / or autoimmune and / or inflammatory diseases such as: SLE, rheumatoid arthritis, polyangiitis, idiopathic thrombocytopenic purpura (ITP), myasthenia gravis Allergic rhinitis and asthma (Di Paolo et al. (2011) Nature Chem. Biol. 7 (1): 41-50; Liu et al. (2011) Jour. Of Pharm. And Exper. Ther. 338 (1): 154 -163). Specific BTK inhibitors have been reported (Liu (2011) Drug Metab. And Disposition 39 (10): 1840-1849; US Patent No. 7,884,108; WO 2010/056875; US Patent No. 7,405,295; US Patent No. 7,393,848; WO 2006 / 053121; US Patent No. 7,947,835; US 2008/0139557; US Patent No. 7,838,523; US 2008/0125417; US 2011/0118233; PCT / US2011 / 050034 "PYRIDINONES / PYRAZINONES, METHOD OF" filed on August 31, 2011 MAKING, AND METHOD OF USE THEREOF "; PCT / US2011 / 050013" PYRIDAZINONES, METHOD OF MAKING, AND METHOD OF USE THEREOF "filed on August 31, 2011; US Serial No. 13 / 102,720 filed on May 6, 2011 "PYRIDONE AND AZA-PYRIDONE COMPOUNDS AND METHODS OF USE"). U.S. Patent No. 8,716,274, which is incorporated herein by reference in its entirety, discloses classes of heteroarylpyridine and azapyridone compounds suitable for inhibiting BTK. Compound (A) depicted below is a specific BTK inhibitor compound: . Compound (A) is: (S) -2- (3 '-(hydroxymethyl) -1-methyl-5-((5- (2-methyl-4- (oxetan-3-yl ) Piperazin-1-yl) pyridin-2-yl) amino) -6- pendantoxy-1,6-dihydro- [3,4'-dipyridine] -2'-yl) -7,7 -Dimethyl-2,3,4,6,7,8-hexahydro-1H-cyclopenta [4,5] pyrrolo [1,2-a] pyrazin-1-one. In the case of any inconsistency between the chemical structure and the chemical name, the chemical structure prevails. All references cited herein, including patent applications and publications, are incorporated herein by reference in their entirety.

Provided herein is a method for treating an individual suffering from an autoimmune or inflammatory disease, the method comprising administering to the individual a therapeutically effective amount of a BTK inhibitor, wherein a sample from the individual has been found to have an elevated content selected from IgJ , Mzb1 and Txndc5 in one or more biomarkers. Also provided herein is a method for treating an autoimmune or inflammatory disease in an individual, the method comprising: (a) determining that a sample from the individual comprises an elevated content of one or more organisms selected from the group consisting of IgJ, Mzb1, and Txndc5 A marker; and (b) administering to a subject an effective amount of a BTK inhibitor, thereby treating an immune disease or disorder. Also provided herein is a method for selecting a therapy for an individual suffering from an autoimmune or inflammatory disease, the method comprising determining the content of one or more biomarkers selected from the group consisting of IgJ, Mzb1, and Txndc5; and based on The content of the biomarker is selected as the drug. This article also provides a method for identifying individuals with autoimmune or inflammatory diseases that are more or less likely to exhibit benefit from treatments comprising BTK inhibitors by measuring a sample from an individual selected from IgJ, Mzb1 The content of one or more biomarkers in a group consisting of Txndc5 and Txndc5, where an increased amount of the biomarker in the sample indicates that the individual is more likely to exhibit benefit from a treatment that includes a BTK inhibitor, or a reduced content of the biomarker indicates the individual It is unlikely to show benefit from a treatment comprising a BTK inhibitor. Also provided herein is an assay for identifying an individual with an autoimmune or inflammatory disease receiving a BTK inhibitor, the method comprising: (a) determining a sample from the individual selected from the group consisting of IgJ, Mzb1, and Txndc5 Content of one or more biomarkers; and (b) it is recommended to administer a BTK inhibitor based on the biomarker content. Also provided herein is a diagnostic kit comprising one or more reagents for determining one or more biomarkers selected from the group consisting of IgJ, Mzb1, and Txndc5 in a sample from an individual suffering from an autoimmune or inflammatory disease. Biomarkers in which elevated levels of biomarkers are detected mean improved efficacy when the subject is treated with a BTK inhibitor, and in which lower or substantially undetectable levels of biomarkers are meant to be used BTK inhibitors are less effective in treating individuals with autoimmune or inflammatory diseases. In some embodiments of the methods provided herein, the method further comprises administering to the individual an effective amount of a BTK inhibitor. In some embodiments of the methods, assays and / or kits provided herein, the sample is a blood sample. In some embodiments of the methods, assays and / or kits provided herein, the BTK inhibitor is an antibody, binding polypeptide, small molecule, and / or polynucleotide. In some embodiments of the methods, assays and / or kits provided herein, the BTK inhibitor is a small molecule. In some embodiments, the small molecule BTK inhibitor is Compound (A) or a pharmaceutically acceptable salt thereof. In some embodiments of the methods, assays and / or kits provided herein, the autoimmune or inflammatory disease is systemic lupus erythematosus. In some embodiments, the autoimmune or inflammatory disease is lupus nephritis. In some embodiments, the autoimmune or inflammatory disease is extrarenal lupus. Biomarkers and their uses for predicting response to treatment with B cell antagonists (e.g., anti-CD20 antibodies) in autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, and lupus have been previously disclosed The method, but not the plasmablast gene tag of the present invention, is not related to BTK inhibition. See WO 2012/118750, the entire contents of which are incorporated herein by reference. As provided herein, transcriptional analysis of a subset of B cells identifies genetic expression tags specific to plasmablasts. In experiments, this label was highly correlated with plasmablast abundance in spikes in vitro. Using FACS analysis on a subset of B cells in SLE patients, paired with RNA sequencing, the gene expression tag of the present invention shows a strong correlation with the frequency of plasmablasts in whole blood. Although plasmablasts represent a small percentage of B cells in the blood, they are responsible for most antibody transcripts found in whole blood mRNAs. Expansion into two additional Phase II clinical trials using the SLEDAI disease activity index to find plasmablast labeling associated with disease activity. In the presence of anti-DNA antibodies, lower levels of complement and leukocytopenia, this relationship is driven by the correlation of plasmablasts. Increased plasmablast labeling is also associated with high levels of interferon activity. Regardless of the severity of the disease, the patient's race / ethnicity also predicts plasmablast labeling. Standard care agents, specifically mycophenolate mofetil, reduce the performance of plasmablast marker genes. For example, treating patients with rituximab causes a significant (but ultimately transient) reduction in plasmablast labeling.

I. definition As used interchangeably herein, "polynucleotide" or "nucleic acid" refers to a polymer of nucleotides of any length and includes DNA and RNA. Nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases and / or their analogs, or can be incorporated into polymers by DNA or RNA polymerase or by synthetic reactions Any of them. Polynucleotides may include modified nucleotides, such as methylated nucleotides and the like. If present, modifications to the nucleotide structure can be imparted before or after assembly of the polymer. The nucleotide sequence may be interspersed with non-nucleotide components. Polynucleotides can be further modified after synthesis, such as in conjunction with a label. Other types of modifications include, for example, "capping"; replacement of one or more naturally occurring nucleotides with analogs; internucleotide modifications, such as having uncharged linkages (e.g., methyl phosphonates, phosphate triesters, phosphorus Amines, carbamates, etc.) and others with charged linkages (e.g., phosphorothioate, phosphorodithioate, etc.), containing proteins such as nucleases, toxins, antibodies, signal peptides, Poly-L-lysine, etc.), flanking parts, those with intercalating agents (e.g., acridine, psoralen, etc.), chelating agents (e.g., metals, radioactive metals, boron, oxidation) Metals, etc.), those containing alkylating agents, those having modified linkages (e.g., alpha-rotomers, etc.), and unmodified forms of polynucleotides. In addition, any hydroxyl group typically present in a sugar may be replaced, for example, by a phosphonate group, a phosphate group, protected by a standard protecting group, or activated to make additional linkages with additional nucleotides, or may be bound to a solid or Semi-solid support. The 5 'and 3' terminal OH can be phosphorylated or partially substituted with an amine or organic capping group of 1 to 20 carbon atoms. Other hydroxy groups can also be derived into standard protecting groups. Polynucleotides may also contain similar forms of ribose or deoxyribose commonly known in the art, including, for example, 2'-O-methyl-, 2'-O-allyl, 2'-fluoro-, or 2 '-Azido-ribose, carbocyclic analogs, alpha-arameloses, epimers (such as arabinose, xyloses, or lyxoses); piperazine Pranose, furanose, sedoheptuloses, acyclic analogs, and abasic nucleoside analogs (such as methyl riboside). One or more phosphodiester bonds may be replaced by alternative linking groups. Such alternative linking groups include, but are not limited to, phosphoric acid via P (O) S ("thiothioate"), P (S) S ("dithioate"), (O) NR₂ (`` Methylamine ''), P (O) R, P (O) OR ', CO or CH<sub>2</sub> ("Formal") embodiment of substitution, wherein each R or R 'is independently H or optionally contains an ether (-O-) bond, aryl, alkenyl, cycloalkyl, cycloalkenyl or aromatic Alkyl substituted or unsubstituted alkyl (1-20 C). Not all bonds in a polynucleotide need to be consistent. The foregoing description applies to all polynucleotides mentioned herein, including RNA and DNA. As used herein, "oligonucleotide" generally refers to a shorter single-stranded polynucleotide, but need not be less than 250 nucleotides in length. Oligonucleotides can be synthetic. The terms "oligonucleotide" and "polynucleotide" are not mutually exclusive. The above description of polynucleotides is equally and fully applicable to oligonucleotides. The term "primer" refers to a single-stranded polynucleotide that is capable of hybridizing to a nucleic acid, and then polymerizing with a complementary nucleic acid, usually by providing a free 3'-OH group. The term "small molecule" refers to any molecule having a molecular weight of about 2000 Daltons or less, preferably about 500 Daltons or less. The terms "host cell", "host cell line", and "host cell culture" are used interchangeably and refer to a cell into which a foreign nucleic acid has been introduced, including descendants of such cells. Host cells include "transformants" and "transformed cells", which include primary transformed cells and descendants derived from them, regardless of the number of generations. Progeny may not have the same nucleic acid content as the mother cell, but may contain mutations. This article includes screening or selecting mutant offspring that have the same function or biological activity against primitively transformed cells. As used herein, the term "vector" refers to a nucleic acid molecule capable of delivering another nucleic acid to which it is linked. The term includes vectors that serve as self-replicating nucleic acid structures as well as vectors incorporated into the genome of a host cell into which they have been introduced. Certain vectors are capable of directing the performance of nucleic acids to which they are operatively linked. These vectors are referred to herein as "expression vectors". An "isolated" antibody is one that has been separated from components of its natural environment. In some embodiments, the antibody is purified to, for example, as determined by, for example, electrophoresis (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatography (e.g., ion exchange or reverse phase HPLC). 95% or 99% purity. For a review of methods for assessing antibody purity, see, for example, Flatman et al.,J. Chromatogr. B 848: 79-87 (2007). "Isolated" nucleic acid refers to a nucleic acid molecule that has been separated from components of its natural environment. An isolated nucleic acid includes a nucleic acid molecule contained in a cell that usually contains a nucleic acid molecule, but the nucleic acid molecule is present outside the chromosome or at a chromosomal location different from its natural chromosomal location. The term "antibody" is used herein in the broadest sense and encompasses a variety of antibody structures including, but not limited to, monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments, as long as they are It is sufficient to exhibit the desired antigen-binding activity. A "blocking" or "antagonist" antibody is an antibody that inhibits or reduces the biological activity of the antigen to which it binds. It is preferred that the blocking or antagonist antibody substantially or completely inhibit the biological activity of the antigen. "Affinity" refers to the strength of the sum of non-covalent interactions between a single binding site of a molecule (eg, an antibody) and its binding partner (eg, an antigen). Unless otherwise indicated, as used herein, "binding affinity" refers to the intrinsic binding affinity that reflects a 1: 1 interaction between members of a binding pair (eg, an antibody and an antigen). The affinity of molecule X for its partner Y is generally expressed by the dissociation constant (Kd). Affinity can be measured by common methods known in the art, including those described herein. Specific illustrative and exemplary embodiments for measuring binding affinity are described below. An "affinity maturity" anti-system refers to an antibody having such changes in one or more hypervariable regions compared to a parent antibody that does not have one or more changes in one or more hypervariable regions (HVR). These changes improve the affinity of the antibody for the antigen. The term "detection" includes any detection method, including direct and indirect detection. As used herein, the term "biomarker" refers to an indicator that can be detected in a sample, such as predictive, diagnostic, and / or prognostic. Biomarkers can serve as indicators of specific subtypes that are characterized by certain molecular, pathological, histological, and / or clinically characteristic diseases or conditions (eg, cancer). In some embodiments, the biomarker is a gene. Biomarkers include, but are not limited to, polynucleotides (e.g., DNA and / or RNA), polypeptides, polypeptide and polynucleotide modifications (e.g., post-translational modifications), carbohydrate and / or glycolipid molecular markers Thing. The terms "biomarker tag", "tag", "biomarker performance tag" or "performance tag" are used interchangeably herein and refer to a biomarker or a combination thereof whose performance is indicative Properties, such as predictive, diagnostic, and / or prognostic. A biomarker tag can serve as an indicator of a particular subtype characterized by a disease or condition (eg, cancer) of certain molecular, pathological, histological, and / or clinical characteristics. In some embodiments, the biomarker tag is a "gene tag." The term "gene tag" is used interchangeably with "gene expression tag" and refers to a polynucleotide, or a combination thereof, that behaves as an indicator, such as predictive, diagnostic, and / or prognostic. In some embodiments, the biomarker tag is a "protein tag." The term "protein tag" is used interchangeably with "protein expression tag" and refers to a polypeptide, or combination thereof, that behaves as an indicator, such as predictive, diagnostic, and / or prognostic. The "amount" or "content" of a biomarker associated with an increased clinical benefit to an individual is the detectable amount in the sample. These can be measured by methods known to those skilled in the art and also disclosed herein. The performance content or amount of the assessed biomarker can be used to determine the response to treatment. The terms "expressed content" or "expressed content" are generally used interchangeably and generally refer to the amount of a biomarker in a biological sample. "Performance" generally refers to the method by which information (e.g., genetic coding and / or epigenetics) is transformed into a structure that exists in and operates in a cell. Thus, as used herein, "performance" may refer to transcription into a polynucleotide, translation into a polypeptide, or even polynucleotide and / or polypeptide modification (eg, post-translational modification of a polypeptide). Transcribed polynucleotides, translated polypeptides, or fragments of polynucleotides and / or polypeptide modifications (e.g., post-translational modifications of polypeptides) should also be considered performance, whether derived from transcripts or degradation resulting from alternative splicing The transcripts are also derived, for example, from post-translational processing of proteolytic peptides. "Expression genes" include genes that are transcribed into polynucleotides such as mRNA and subsequently translated into polypeptides, and also genes that are transcribed into RNA but not translated into polypeptides (eg, transfer and ribosomal RNA). "High performance", "High performance content" or "High content" refers to a biomarker in an individual relative to a control (such as an individual or an individual without an illness or disorder (e.g., cancer) or an internal control (e.g., housekeeper Biomarkers)) increased expression or increased content. "Reduced performance", "reduced performance content" or "reduced content" refers to a biomarker in an individual relative to a control (such as an individual or an individual without an illness or disorder (e.g., cancer) or an internal control (e.g., housekeeper Biomarkers)). In some embodiments, the reduced performance is minimal or no performance. In certain embodiments, the term "under reference content" refers to the content of a biomarker in a sample from an individual or patient that is substantially equivalent to the reference content or refers to a difference of up to 1%, up to 2% from the reference content , Up to 3%, up to 4%, up to 5%. In some embodiments, the reference content is an intermediate content of a biomarker in a reference population. In some embodiments, the reference content of the marker is the average content of the marker in the reference population. In some embodiments, the reference content of the marker is the average content of the marker in the reference population. In certain embodiments, the term "above reference content" refers to at least 5%, 10%, 20%, 25%, 30% above the reference content as determined by the methods described herein relative to the reference content. , 40%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 100% or more of the biomarker content in a sample from an individual or patient. In some embodiments, the reference content is an intermediate content in a reference population. In some embodiments, the reference content of the marker is the average content of the marker in the reference population. In certain embodiments, the term "below the reference content" means at least 5%, 10%, 20%, 25%, 30% below the reference content, as determined by the methods described herein, relative to the reference content. , 40%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 100% or more of the biomarker content in a sample from an individual or patient. In some embodiments, the reference content is an intermediate content in a reference population. In some embodiments, the reference content of the marker is the average content of the marker in the reference population. In some embodiments, the reference content of the marker is the average content of the marker in the reference population. The term "housekeeper biomarker" refers to a biomarker or population of biomarkers (eg, polynucleotides and / or polypeptides) that are typically similarly found in all cell types. In some embodiments, the housekeeping biomarker is a "housekeeping gene". A "housekeeping gene" refers herein to a gene or group of genes that encodes a protein that is essential for the maintenance of cell function and is typically similarly present in all cell types. As used herein, "amplification" generally refers to a method of generating multiple copies of a desired sequence. "Multiple copies" means at least two copies. "Duplicate" does not necessarily mean a perfect sequence that is complementary or consistent with the template sequence. For example, replicas may include nucleotide analogs, such as deoxyinosine, intentional sequence changes (such as sequence changes introduced via primers that include sequences that are hybridizable to the template but are not complementary), and / or occur during amplification Sequence error. The term "multiplex PCR" refers to a single PCR reaction performed on a nucleic acid obtained from a single source (eg, an individual) using more than one primer for the purpose of amplifying two or more DNA sequences in a single reaction. The "stringency" of the hybridization reaction can be easily determined by those skilled in the art, and is usually calculated empirically depending on the length of the probe, washing temperature, and salt concentration. In general, longer probes require higher temperatures for proper annealing, while shorter probes require lower temperatures. When complementary strands are present in an environment below their melting temperature, hybridization usually depends on the ability of the denatured DNA to reanneal. The higher the desired degree of homology between the probe and the hybridizable sequence, the higher the relative temperature at which it can be used. Therefore, it can be seen that the higher the relative temperature will tend to make the reaction conditions more stringent, and the temperature will also decrease. For additional details and explanations of the stringency of hybridization reactions, see Ausubel et al., Current Protocols in Molecular Biology, Wiley Interscience Publishers, (1995). As defined herein, "stringent conditions" or "high stringency conditions" can be identified by: (1) the use of low ionic strength and high temperature for washing, for example at 50 ° C, 0.015 M sodium chloride / 0.0015 M sodium citrate / 0.1% sodium lauryl sulfate; (2) using a denaturing reagent such as formamidine during hybridization, for example, at 42 ° C, with 0.1% bovine serum albumin / 0.1% ficol (Ficoll) /0.1% polyvinylpyrrolidone / 50 mM sodium phosphate buffer at pH 6.5 and 50% (v / v) formamidine of 750 mM sodium chloride and 75 mM sodium citrate; or (3) at 42 50% formamidine, 5 × SSC (0.75 M NaCl, 0.075 M sodium citrate), 50 mM sodium phosphate (pH 6.8), 0.1% sodium pyrophosphate, 5 × Denhardt's solution at ℃ , Sonicated salmon sperm DNA (50 μg / ml), 0.1% SDS and 10% dextran sulfate in hybridization overnight, with 42 ° C in 0.2 × SSC (sodium chloride / sodium citrate) A 10 minute wash was followed by a 10 minute high stringency wash consisting of 0.1 x SSC containing EDTA at 55 ° C. "Medium stringent conditions" can be identified as described by Sambrook et al., Molecular Cloning: A Laboratory Manual, New York: Cold Spring Harbor Press, 1989, and include the use of washing solutions and more relaxed than those described above. Hybridization conditions (eg, temperature, ionic strength, and% SDS). Examples of moderately stringent conditions are incubation overnight at 37 ° C in a solution containing: 20% formamidine, 5 × SSC (150 mM NaCl, 15 mM trisodium citrate), 50 mM sodium phosphate (pH 7.6), 5 × Dunhart's solution, 10% dextran sulfate, and 20 mg / ml denatured sheared salmon sperm DNA, and then the filtrate was washed in 1 × SSC at about 37-50 ° C. Those skilled in the art will know how to adjust temperature, ionic strength, etc. as necessary to accommodate factors such as probe length and the like. The term "diagnosis" is used herein to refer to the identification or classification of a molecular or pathological condition, disease, or condition (eg, cancer). For example, "diagnosis" can refer to the identification of a specific type of cancer. "Diagnosis" may also refer to a subtype characterized, for example, by histopathological criteria, or by the performance of a molecular feature (e.g., by a biomarker (e.g., a specific gene or protein encoded by the gene) or a combination thereof ) Classify cancer specific subtypes. The term "assisted diagnosis" refers herein to a method that assists in making a clinical determination regarding the presence or nature of a particular type of symptom or condition of a disease or disorder (eg, cancer). For example, a method to assist in the diagnosis of a disease or condition (e.g., cancer) may include measuring certain biomarkers in a biological sample from an individual. As used herein, the term "sample" refers to a composition obtained or derived from a subject and / or individual of interest, which contains, for example, discriminable and / or physical, biochemical, chemical and / or physiological characteristics Cells and / or other molecular entities identified. For example, the phrase "disease sample" and its variants refers to any sample obtained from a subject of interest that is expected or known to contain cells and / or molecular entities with characteristics to be identified. Samples include (but are not limited to) native or cultured cells or cell lines, cell supernatants, cell lysates, platelets, serum, plasma, vitreous fluid, lymph fluid, synovial fluid, follicular fluid, semen, amniotic fluid , Milk, whole blood, blood-derived cells, urine, cerebrospinal fluid, saliva, sputum, tears, sweat, mucus, tumor lysates and tissue culture media, tissue extracts (such as homogenized tissue), tumor tissue, Cell extracts and combinations thereof. "Tissue sample" or "cell sample" means a collection of similar cells obtained from the tissue of a subject or individual. The source of the tissue or cell sample may be solid tissue, such as: from fresh, frozen and / or preserved organs, tissue samples, biopsies and / or extracts; blood or any blood component such as plasma; body fluids such as cerebrospinal fluid , Amniotic fluid, peritoneal fluid, or interstitial fluid; cells from a subject at any time during pregnancy or development. Tissue samples can also be native or cultured cells or cell lines. Optionally, a tissue or cell sample is obtained from the diseased tissue / organ. Tissue samples may contain compounds such as preservatives, anticoagulants, buffers, fixatives, nutrients, antibiotics, or the like, which do not naturally intermix with tissues of nature. As used herein, "reference sample", "reference cell", "reference tissue", "control sample", "control cell" or "control tissue" means a sample, cell, tissue, standard used for comparison purposes Or content. In one embodiment, the reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is obtained from a healthy and / or disease-free portion (e.g., tissue or cell) of the same subject or individual's body . For example, healthy and / or non-diseased cells or tissues near diseased cells or tissues (eg, cells or tissues near tumors). In another embodiment, the reference sample is obtained from untreated tissue and / or cells of the same subject or individual's body. In yet another embodiment, the reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is obtained from a healthy and / or non-diseased part of the body of another individual who is not the subject or individual ( (E.g., tissue or cell). In yet another embodiment, the reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is obtained from untreated tissue and / or cells of the body of another individual who is not the subject or individual. For the purposes of this document, a "slice" of a tissue sample means a single portion or fragment of a tissue sample, such as a thin layer of tissue or cells cut from a tissue sample. It should be understood that multiple sections of a tissue sample can be used and analyzed, with the limitation being that it should be understood that the same section of a tissue sample can be analyzed in both morphology and molecular content, or in terms of both polypeptides and polynucleotides analysis. "Correlate / correlating" means comparing the performance and / or results of the first analysis or protocol with the performance and / or results of the second analysis or protocol in any way. For example, we can use the results of the first analysis or protocol for the second protocol and / or we can use the results of the first analysis or protocol to determine whether the second analysis or protocol should be performed. Regarding examples of polynucleotide analysis or protocol, we can use the results of the polynucleotide performance analysis or protocol to determine whether a particular treatment protocol should be performed. "Individual response" or "response" can be assessed using any endpoint that indicates an individual benefit, including (but not limited to): (1) inhibiting the progression of disease (e.g., cancer progression) to a certain extent, including slowing Complete suppression; (2) Reduction of tumor size; (3) Inhibition (i.e., reduction, slowing, or completion of suppression) of cancer cells penetrating close to surrounding organs and / or tissues; (4) Inhibition (i.e., reduction, reduction (Slow or complete suppression) lesions; (5) relieve to some extent one or more symptoms associated with a disease or disorder (e.g., cancer); (6) increase the length of progression-free survival; and / or (7) during treatment The given time point is followed to reduce mortality. As used herein, the term "substantially the same" means a sufficiently high degree of similarity between two values, so that in the case of biological characteristics measured by such values (e.g., Kd value or performance), familiarity with this The skilled person will consider the difference between the two values to be minimal or non-biological and / or statistically significant. The difference between the two values is, for example, less than about 50%, less than about 40%, less than about 30%, less than about 20%, and / or less than about 10%, which varies with reference / comparative values. As used herein, the phrase "substantially different" indicates a sufficiently high degree of difference between the two values, so that in the case of biological characteristics measured by such values (e.g., Kd value), familiarize yourself with this The skilled person will consider the difference between these two values to be statistically significant. The difference between the two values is, for example, greater than about 10%, greater than about 20%, greater than about 30%, greater than about 40%, and / or greater than about 50%, which varies with the value of the reference / comparison molecule. The phrase "label" as used herein means a detectable compound or composition. The label is typically bound or fused directly or indirectly to a reagent, such as a polynucleotide probe or antibody, and helps to detect the reagent to which it is bound or fused. The label itself can be detectable (e.g., a radioisotope label or a fluorescent label), or in the case of an enzyme label, it can catalyze a chemical change in the host compound or composition to produce a detectable product. An "effective amount" of an agent is an amount effective to achieve the desired therapeutic or preventive result at the required dose and time period. The "therapeutically effective amount" of a substance / molecule (agonist or antagonist) can vary depending on factors such as the disease condition, age, sex, and weight of the individual, and the substance / molecule (agonist or antagonist) in the individual The ability to trigger the desired reaction. A therapeutically effective amount is also one in which any therapeutically beneficial effect exceeds any toxic or deleterious effect of the substance / molecule (agonist or antagonist). A "prophylactically effective amount" means an amount effective to achieve a desired preventive result at the required dose and time period. Since individuals use prophylactic doses before or early in the disease, a prophylactically effective amount is usually (but not necessarily) smaller than a therapeutically effective amount. The term "pharmaceutical formulation" refers to a formulation in a form that permits the biological activity of the active ingredients contained therein to be effective and which does not contain other components that have unacceptable toxicity to the individual to whom the formulation is to be administered. "Pharmaceutically acceptable carrier" means an ingredient in a pharmaceutical formulation that is not toxic to an individual other than the active ingredient. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives. As used herein, "treatment" (and its grammatical variations, such as "treat / treating") refers to a clinical intervention that attempts to alter the natural course of an individual being treated, and may be for prevention or control purposes or Performed during the course of clinical pathology. The required therapeutic effects include, but are not limited to, preventing the occurrence or recurrence of a disease, alleviating symptoms, alleviating any direct or indirect pathological consequences of the disease, preventing cancer metastasis, slowing the rate of disease progression, improving or alleviating the disease condition, and alleviating or improving the prognosis. In some embodiments, the antibodies are used to delay or slow disease progression. As used in this application, the term "prodrug" refers to a precursor or derivative of a pharmaceutically active substance that is less cytotoxic to tumor cells than the parent drug and is capable of being activated enzymatically or Conversion to a more active parent form. See, e.g., Wilman, "Prodrugs in Cancer Chemotherapy"Biochemical Society Transactions , 14, pp. 375-382, 615th Meeting Belfast (1986) and Stella et al., "Prodrugs: A Chemical Approach to Targeted Drug Delivery",Directed Drug Delivery Borchardt et al., Eds., Pp. 247-267, Humana Press (1985). Prodrugs of the present invention include (but are not limited to) phosphate-containing prodrugs, thiophosphate-containing prodrugs, sulfate-containing prodrugs, peptide-containing prodrugs, D-amino acid modified prodrugs, and glycosylated prodrugs , Β-lactamamine-containing prodrugs, optionally substituted phenoxyacetamide prodrugs, or optionally substituted phenylacetamide prodrugs, 5-fluorocytosine and can be converted into more active Other 5-fluorouridine prodrugs of cytotoxic free drugs. Examples of cytotoxic drugs that can be derived into prodrug forms for use in the present invention include, but are not limited to, their chemotherapeutic agents described above. "Individual" or "subject" is a mammal. Mammals include, but are not limited to, domestic animals (e.g., cattle, sheep, cats, dogs, and horses), primates (e.g., human and non-human primates, such as monkeys), rabbits, and rodents (e.g., , Mouse and rat). In certain embodiments, the individual or subject is human. The term "simultaneously" is used herein to refer to the administration of two or more therapeutic agents, wherein at least a portion of the administrations overlap in time. Thus, simultaneous administration includes a dosing regimen when administration of one or more agents is continued after interruption of administration of one or more other agents. "Reducing or inhibiting" means the ability to reduce overall by 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95% or more. Reduction or inhibition can refer to the symptoms of the condition being treated, the presence or size of cancer metastases, or the size of the primary tumor. The term "pharmaceutical instructions" is used to refer to the instructions normally included in the commercial packaging of therapeutic products, which contain indications, usage, dosage, administration, combination therapy, contraindications and / Or warnings. "Article of manufacture" is any manufactured article (e.g., a package or container) or kit containing at least one reactant, such as a drug used to treat a disease or disorder (e.g., cancer) or used to specifically detect as described herein Biomarker probe. In some embodiments, the article of manufacture or kit is marketed, distributed, or sold in the form of a unit for performing the methods described herein. The phrase "based on" as used in this article means that information about one or more biomarkers is used to inform treatment decisions and information provided on the drug label or sales / promotion guide. As understood by those skilled in the art, references to "about" a value or parameter herein include (and describe) embodiments directed to that value or parameter itself. For example, a reference to "about X" includes a description of "X" itself. It should be understood that the aspects and embodiments described herein include "composition" and / or "substantially composed of" aspects and embodiments. Unless otherwise specified, as used herein, the singular forms "a / an" and "the" include plural references. II. Method and use Provided herein are methods for utilizing plasmablast biomarkers. In particular, methods using BTK inhibitors and plasmablast biomarkers. For example, methods are provided for treating an individual with a disease or condition, the methods comprising administering to the individual effective treatment if the individual has been found to have the presence and / or increased content of a plasmablast biomarker Amount of BTK inhibitor. In addition, provided herein is a method for treating a disease or condition in an individual, the method comprising: determining that a sample from the individual contains an elevated content of plasmablast biomarkers, and administering to the individual an effective amount of a BTK inhibitor, by This treats a disease or condition. In some embodiments, the plasmablast biomarker is selected from the group consisting of the following genetic tags: IgJ, Mzb1, and Txndc5. In some embodiments, the genes of IgJ, Mzb1 and Txndc5 are expressed as polypeptides, which are determined by measuring the mRNA content of the gene in a patient's blood relative to a reference content. In some embodiments, the disease or disorder is an autoimmune or inflammatory disease or disorder. In some embodiments, the disease or disorder is SLE. In some embodiments, the disease or condition is lupus nephritis. In some embodiments, the disease or condition is extrarenal lupus. Provided herein are methods of treating a disease or condition in an individual, the methods comprising administering to the individual an effective amount of a BTK inhibitor, wherein the treatment is based on the presence and / or increased content of a plasmablast biomarker in a sample from the individual . In some embodiments, the plasmablast biomarker is a manifestation of one or more of IgJ, Mzb1, and Txndc5. In some embodiments, the genes of IgJ, Mzb1 and Txndc5 are expressed as polypeptides, which are determined by measuring the mRNA content of the gene in a patient's blood relative to a reference content. In some embodiments, the disease or disorder is an autoimmune or inflammatory disease or disorder. In some embodiments, the disease or disorder is SLE. In some embodiments, the disease or condition is lupus nephritis. In some embodiments, the disease or condition is extrarenal lupus. Furthermore, provided herein are methods for selecting a therapy for an individual suffering from a disease or disorder, the methods comprising determining the presence and / or content of a plasmablast biomarker and based on the presence and / or content of the biomarker And choose drugs. In some embodiments, the drug is selected based on elevated levels of plasmablast biomarkers. In some embodiments, the plasmablast biomarker is selected from the group consisting of the following genetic tags: IgJ, Mzb1, and Txndc5. In some embodiments, the genes of IgJ, Mzb1 and Txndc5 are expressed as polypeptides, which are determined by measuring the mRNA content of the gene in a patient's blood relative to a reference content. In some embodiments, the disease or disorder is an autoimmune or inflammatory disease or disorder. In some embodiments, the disease or disorder is SLE. In some embodiments, the disease or condition is lupus nephritis. In some embodiments, the disease or condition is extrarenal lupus. Provided herein are methods for identifying individuals with a disease or disorder that are more or less likely to exhibit benefit from treatment comprising a BTK inhibitor, the method comprising: determining the presence of plasmablast biomarkers in a sample from the individual and / Or content where the presence and / or elevated content of plasmablast biomarkers in a sample indicates that the individual is more likely to exhibit benefit from treatment comprising a BTK inhibitor, or the absence and / or reduction of plasmablast biomarkers The amount indicates that the individual is unlikely to exhibit benefit from a treatment comprising a BTK inhibitor. In some embodiments, the plasmablast biomarker is selected from the group consisting of the following genetic tags: IgJ, Mzb1, and Txndc5. In some embodiments, the genes of IgJ, Mzb1 and Txndc5 are expressed as polypeptides, which are determined by measuring the mRNA content of the gene in a patient's blood relative to a reference content. In some embodiments, the disease or disorder is an autoimmune or inflammatory disease or disorder. In some embodiments, the disease or disorder is SLE. In some embodiments, the disease or condition is lupus nephritis. In some embodiments, the disease or condition is extrarenal lupus. Also provided herein is an assay for identifying an individual with a disease or disorder receiving a BTK inhibitor, the method comprising: (a) determining the presence and / or content of a plasmablast biomarker in a sample from the individual; ( b) BTK inhibitors are recommended based on the presence and / or content of plasmablast biomarkers. In some embodiments, BTK inhibitors are recommended based on elevated levels of plasmablast biomarkers. In some embodiments, the plasmablast biomarker is selected from the group consisting of the following genetic tags: IgJ, Mzb1, and Txndc5. In some embodiments, the genes of IgJ, Mzb1 and Txndc5 are expressed as polypeptides, which are determined by measuring the mRNA content of the gene in a patient's blood relative to a reference content. In some embodiments, the disease or disorder is an autoimmune or inflammatory disease or disorder. In some embodiments, the disease or disorder is SLE. In some embodiments, the disease or condition is lupus nephritis. In some embodiments, the disease or condition is extrarenal lupus. Provided herein is a diagnostic kit comprising one or more reagents for determining the content of a plasmablast biomarker in a sample from an individual having a disease or condition, wherein the presence of the plasmablast biomarker is detected And / or elevated levels mean improved efficacy when treating individuals with BTK inhibitors, and where a lower or substantially undetectable level of plasmablast biomarkers was detected meant that patients with BTK inhibitors were treated The effect is reduced in individuals with the disease. Articles are also provided herein that include a pharmaceutical composition containing a BTK inhibitor and a package insert packaged together, the package insert indicating that the BTK inhibitor is used to treat a disease or condition based on the performance of plasmablast biomarkers Patient. In some embodiments, the plasmablast biomarker is selected from the group consisting of the following genetic tags: IgJ, Mzb1, and Txndc5. In some embodiments, the genes of IgJ, Mzb1 and Txndc5 are expressed as polypeptides, which are determined by measuring the mRNA content of the gene in a patient's blood relative to a reference content. In some embodiments, the disease or disorder is an autoimmune or inflammatory disease or disorder. In some embodiments, the disease or disorder is SLE. In some embodiments, the disease or condition is lupus nephritis. In some embodiments, the disease or condition is extrarenal lupus. In addition, provided herein are methods for treating a disease or condition in an individual, the methods comprising administering to the individual an effective amount of a BTK inhibitor, and evaluating one or more plasma mothers in a sample from the individual during treatment with the BTK inhibitor The content of a cell biomarker (eg, compared to a reference). Methods of treating a disease or condition in an individual are also provided, the methods comprising administering to the individual an effective amount of a BTK inhibitor, wherein the treatment is based on the content of one or more plasmablast biomarkers in the sample from the individual (e.g., Compared to reference). Provided is a method for monitoring a response in a subject treated with a BTK inhibitor, the method comprising determining the content of one or more plasmablast biomarkers in a sample from the individual, wherein the reduced content of one or more plasmablasts A cell biomarker (e.g., compared to a reference) indicates that an individual is more likely to respond to a treatment comprising a BTK inhibitor with one or more plasmablast biomarkers that increase the content and / or are substantially the same as the pre-treatment content An object (eg, compared to a reference) indicates that the individual is unlikely to respond to a treatment comprising a BTK inhibitor. In some embodiments, the plasmablast biomarker is selected from the group consisting of the following genetic tags: IgJ, Mzb1, and Txndc5. In some embodiments, the genes of IgJ, Mzb1 and Txndc5 are expressed as polypeptides, which are determined by measuring the mRNA content of the gene in a patient's blood relative to a reference content. In some embodiments, the disease or disorder is an autoimmune or inflammatory disease or disorder. In some embodiments, the disease or disorder is SLE. In some embodiments, the disease or condition is lupus nephritis. In some embodiments, the disease or condition is extrarenal lupus. Also provided is a method of determining whether an individual with a disease or condition should continue or discontinue treatment with a BTK inhibitor, the method comprising measuring the content of one or more plasmablast biomarkers in a sample from the individual, which increases Determination of one or more plasmablast biomarkers (e.g., compared to a reference) at levels and / or levels substantially the same as before treatment. Individuals should discontinue treatment with a BTK inhibitor and reduce the level of one or more plasma. Blast cell biomarkers (eg, compared to a reference) determine that an individual should continue treatment with a BTK inhibitor. In some embodiments, the plasmablast biomarker is selected from the group consisting of the following genetic tags: IgJ, Mzb1, and Txndc5. In some embodiments, the genes of IgJ, Mzb1 and Txndc5 are expressed as polypeptides, which are determined by measuring the mRNA content of the gene in a patient's blood relative to a reference content. In some embodiments, the disease or disorder is an autoimmune or inflammatory disease or disorder. In some embodiments, the disease or disorder is SLE. In some embodiments, the disease or condition is lupus nephritis. In some embodiments, the disease or condition is extrarenal lupus. In some embodiments, the method comprises: (a) measuring the RNA content of one, two, or three biomarkers selected from the group consisting of IgJ, TXNDC5, and MZB1 in a biological sample from a patient; (b) adding (a) The RNA content measured in the comparison with the reference content; and (c) when the RNA content measured in (a) is higher than the reference content, the patient is identified as more likely to benefit from BTK inhibitor therapy. In some embodiments, the RNA is mRNA. In some embodiments, measuring mRNA content comprises amplification. In some embodiments, measuring mRNA content comprises quantitative PCR. In some embodiments, measuring the mRNA content includes amplifying the mRNA and detecting the amplified product, thereby measuring the mRNA content. In some embodiments, the reference content is the intermediate content of the corresponding marker in the reference population. In some embodiments, the reference content of the marker is an intermediate content of the marker in the reference population. In any of the embodiments described herein, the reference content may be the average content of the corresponding marker in the reference population. In some embodiments, the reference content of the marker is the average content of the marker in the reference population. Non-limiting exemplary reference populations include patients with immune or inflammatory diseases, healthy individuals, and populations including healthy individuals and patients with immune or inflammatory diseases. In some embodiments, the reference population comprises patients with SLE. In some embodiments, the method of analyzing or detecting a biomarker has a p-value of less than 0.05. In some embodiments, the method has a specificity greater than 80%. In some embodiments, the method has a sensitivity above 80%. In some embodiments, the method has an ROC greater than 70%. In some embodiments, the method has an AUC greater than 70%. In some embodiments, the method has a positive prediction value above 70%. In some embodiments, the method has a negative predicted value above 70%. In some embodiments, the reference gene performance profile is from subjects in a reference population of patients and / or healthy volunteers. In some embodiments, the comparing step includes at least one of: comparing digital images of performance profiles and comparing a database of performance data. In some embodiments of any of the above methods, the plasmablast biomarker is IgJ. In some embodiments of any of the above methods, the plasmablast biomarker is Mzb1. In some embodiments of any of the above methods, the plasmablast biomarker is Txndc5. In some embodiments of any of the above methods, the one or more plasmablast biomarkers are IgJ and Mzb1. In some embodiments of any of the above methods, the one or more plasmablast biomarkers are IgJ and Txndc5. In some embodiments of any of the above methods, the one or more plasmablast biomarkers are Txndc5 and Mzb1. In some embodiments of any of the above methods, the one or more plasmablast biomarkers are IgJ, Mzb1, and Txndc5. In some of the above embodiments, the sample is a urine sample. In some embodiments, the sample is a blood sample. In some embodiments, the biological sample is selected from the group consisting of blood, serum, plasma, and peripheral blood mononuclear cells (PBMC). In some embodiments, the biological sample is RNA obtained from blood, such as whole blood or a cell segment of blood, such as PBMC. In some embodiments, the biological sample is serum or plasma. Samples can be taken before, during or after treatment. Samples can be obtained from patients who are suspected of or diagnosed with SLE or other immune or inflammatory diseases and therefore may require treatment. Alternatively, the sample may be obtained from a normal individual who is not suspected of having any disease. In some embodiments, RNA is extracted from a biological sample described herein prior to detecting or measuring the mRNA content of the marker. The presence and / or expression content / quantity of a biomarker can be determined qualitatively and / or quantitatively based on any suitable criteria known in the art, including (but not limited to) DNA, mRNA, cDNA, protein, protein fragments, and / Or the number of gene copies. In some embodiments, the presence and / or expression content / amount of the biomarker in the first sample is increased compared to the presence / absence and / or expression content / amount in the second sample. In certain embodiments, the presence / absence and / or performance content / amount of the biomarker in the first sample is reduced compared to the presence and / or performance content / amount in the second sample. In some embodiments, the second sample is a reference sample, a reference cell, a reference tissue, a control sample, a control cell, or a control tissue. Described herein are additional disclosures for determining the presence / absence and / or expression content / amount of a gene. In some embodiments of any of the methods, high performance refers to comparison to a reference sample, reference cell, reference tissue, control sample, control cell, or control tissue by methods known in the standard art, such as those described herein They are described) 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% of the biomarker (e.g., protein or nucleic acid (e.g., gene or mRNA)) detected The overall increase is any one of%, 90%, 95%, 96%, 97%, 98%, 99% or more. In certain embodiments, high performance refers to an increase in the expression content / amount of a biomarker in a sample, where the increase is a corresponding biomarker in a reference sample, a reference cell, a reference tissue, a control sample, a control cell, or a control tissue The expression content / amount is at least about 1.5 ×, 1.75 ×, 2 ×, 3 ×, 4 ×, 5 ×, 6 ×, 7 ×, 8 ×, 9 ×, 10 ×, 25 ×, 50 ×, 75 × or Any of 100 ×. In some embodiments, high performance refers to about 1.5 times, about 1.75 times, about 2 times compared to a reference sample, reference cell, reference tissue, control sample, control cell, control tissue, or internal control (e.g., a housekeeping gene) , About 2.25 times, about 2.5 times, about 2.75 times, about 3.0 times, or about 3.25 times the overall increase. In some embodiments of any of the methods, reduced performance refers to a comparison of a reference sample, reference cell, reference tissue, control sample, control cell, or control tissue by a method known in the standard, such as Those described) are about 10%, 20%, 30%, 40%, 50%, 60%, 70%, biomarker (e.g., protein or nucleic acid (e.g., gene or mRNA)) detected, The overall reduction is any of 80%, 90%, 95%, 96%, 97%, 98%, 99% or more. In some embodiments, the reduced performance refers to a decrease in the expression content / amount of the biomarker in the sample, wherein the decrease is the performance of the corresponding biomarker in the reference sample, reference cell, reference tissue, control sample, control cell, or control tissue. The content / amount is at least about 0.9 ×, 0.8 ×, 0.7 ×, 0.6 ×, 0.5 ×, 0.4 ×, 0.3 ×, 0.2 ×, 0.1 ×, 0.05 ×, or 0.01 ×. The presence and / or performance content / amount of various biomarkers in a sample can be analyzed by a number of methods, many of which are known in the art and familiar to those skilled in the art, including (but not limited to) immunohistochemistry ( (`` IHC ''), Western blot analysis, immunoprecipitation, molecular binding analysis, ELISA, ELIFA, fluorescence activated cell sorting (`` FACS ''), MassARRAY, proteomics research, blood-based quantitative analysis ( (E.g., serum ELISA), biochemical enzyme activity analysis, in situ hybridization, Southern analysis, Northern analysis, whole genome sequencing, polymerase chain reaction (`` PCR '') (including quantitative real-time PCR (`` qRT-PCR ") and other amplification-type detection methods, such as branched-chain DNA, SISBA, TMA, and the like), RNA-Seq, FISH, microarray analysis, gene performance profiling, and / or continuous analysis of gene performance ("SAGE") and any of a variety of analyses that can be performed by protein, gene, and / or tissue array analysis. Typical protocols for assessing the status of genes and gene products are found in, for example, Ausubel et al., 1995, Current Protocols In Molecular Biology, Units 2 (Northern Blotting), 4 (Southern Blotting), 15 (Immunoblotting), and 18 (PCR Analysis). Multiplex immunoassays may also be used, such as those available from Rules Based Medicine or Meso Scale Discovery ("MSD"). In some embodiments, the presence and / or expression content / amount of a biomarker is determined using a method comprising: (a) performing a gene performance profiling on a sample (such as a subject's cancer sample), PCR (such as rtPCR), RNA-seq, microarray analysis, SAGE, MassARRAY technology or FISH; and b) determine the presence and / or performance content / amount of biomarkers in the sample. In some embodiments, a microarray method includes using a microarray wafer having one or more nucleic acid molecules that can hybridize to a nucleic acid molecule encoding the gene described above under stringent conditions, or having a nucleic acid molecule that can bind to the gene encoded by the gene. One or more polypeptides (such as peptides or antibodies) of one or more proteins. In one embodiment, the PCR method is qRT-PCR. In one embodiment, the PCR method is multiplex PCR. In some embodiments, gene performance is measured by a microarray. In some embodiments, gene performance is measured by qRT-PCR. In some embodiments, gene performance is measured by multiplex PCR. Methods for assessing mRNA in cells are well known and include, for example, hybridization analysis using complementary DNA probes (such as in situ hybridization using labeled RNA probes specific for one or more genes, northern blots And related technologies) and various nucleic acid amplification analyses (such as RT-PCR using complementary primers specific for one or more of the genes, and other amplification type detection methods, such as branched-chain DNA, SISBA, TMA, and Its analogs). Samples from mammals may be suitably analyzed for mRNA using northern, spot blotting, or PCR analysis. In addition, these methods may include one or more steps that allow the determination of the content of a target mRNA in a biological sample (e.g., by simultaneously checking the content of a comparative control mRNA sequence of a "housekeeper" gene such as a member of the actin family) ). Optionally, the sequence of the amplified target cDNA can be determined. Optional methods include protocols for examining or detecting mRNAs, such as target mRNAs, in tissue or cell samples by microarray technology. Using nucleic acid microarrays, test and control mRNA samples from test and control tissue samples are reverse transcribed and labeled to generate cDNA probes. The probe is then hybridized to a nucleic acid array immobilized on a solid support. The array is configured so that the sequence and position of the members of the array are known. For example, a series of genes whose performance is related to the clinical benefit of increased or decreased anti-angiogenesis therapy can be arranged on a solid support. Hybridization of a labeled probe with a particular array member indicates that a sample of the derived probe expresses that gene. According to some embodiments, the presence and / or expression content / amount is measured by observing the protein expression content of the aforementioned genes. In certain embodiments, the method comprises contacting a biological sample with an antibody of a biomarker as described herein under conditions that allow binding of the biomarker, and detecting whether a complex is formed between the antibody and the biomarker. This method can be an in vitro or in vivo method. In one embodiment, the antibody is used to select a subject suitable for therapy with a BTK inhibitor, such as to select an individual's biomarker. In certain embodiments, IHC and staining protocols are used to detect the presence and / or performance content / amount of biomarker proteins in a sample. IHC staining of tissue sections has been shown to be a reliable method for determining or detecting the presence of proteins in a sample. In some embodiments of any of the methods, assays, and / or sets, the plasmablast biomarker is selected from one or more of IgJ, Mzb1, and Txndc5. In some embodiments, IgJ, Mzb1 and / or Txndc5 are detected by immunohistochemistry. In some embodiments, the high performance of plasmablast biomarkers in samples from individuals is high protein performance, and in other embodiments the IHC assay is used. In one embodiment, the performance content of a biomarker is determined using a method comprising: (a) performing an IHC analysis on a sample having an antibody; and b) determining the performance content of a biomarker in the sample. In some embodiments, IHC staining intensity is determined relative to a reference. In some embodiments, the reference is a reference value. In some embodiments, the reference is a reference sample (eg, a control cell line stained sample). In some embodiments, the tissue is kidney tissue. In other embodiments, the above technique is performed using fluorescence in situ hybridization instead of IHC. IHC can be performed in combination with other techniques, such as morphological staining and / or fluorescent in situ hybridization. Two IHC methods are available; direct analysis and indirect analysis. According to the first analysis, the binding of the antibody to the target antigen was directly determined. This direct analysis uses labeled reactants, such as fluorescently labeled or enzyme-labeled primary antibodies, which can be visually inspected without the need for additional antibody interactions. In a typical indirect analysis, the unbound primary antibody is bound to the antigen and then the labeled secondary antibody is bound to the primary antibody. When the secondary antibody is bound to the enzyme label, a chromogenic or fluorescent substrate is added to provide visual inspection of the antigen. Because several secondary antibodies can react with different epitopes on the primary antibody, signal amplification occurs. Primary and / or secondary antibodies for IHC will usually be labeled by a detectable moiety. Several markers are available, which can be broadly grouped into the following categories: (a) Radioisotopes, such as³⁵ S,¹⁴ C,¹²⁵ I,³ H and¹³¹ I; (b) colloidal gold particles; (c) fluorescent labels, including (but not limited to) rare earth chelates (fluorene chelates), Texas Red, rhodamine , Fluorescein, dansyl, Lissamine, umbelliferone, phycocrytherin, phycocyanin or commercially available fluorescent groups, Derivatives such as SPECTRUM ORANGE7 and SPECTRUM GREEN7 and / or any one or more of the above; (d) various enzyme substrates are labeled as available signatures and US Patent No. 4,275,149 provides a review of some of these. Examples of enzyme labels include luciferase (e.g., firefly luciferase and bacterial luciferase; U.S. Patent No. 4,737,456), luciferin, 2,3-dihydrophthalazinedione, malate Catalase, urease, peroxidase (such as horseradish peroxidase (HRPO)), alkaline phosphatase, β-galactose, amylase, lysozyme, sugar oxidase (e.g., glucose oxidase, Galactose oxidase and glucose-6-phosphate dehydrogenase), heterocyclic oxidases (such as urase and xanthine oxidase), lactoperoxidase, microperoxidase and the like. Examples of the enzyme substrate combination include, for example, horseradish peroxidase (HRPO) having a hydroperoxidase as a substrate; alkaline phosphatase (AP) having p-nitrophenyl phosphate as a color substrate; and Β-D-galactose (for example, p-nitrophenyl-β-D-galactose) or fluorescein (for example, 4-methylumbellyl-β-D-galactose) β-D-Gal). For a general review of these, see US Patent Nos. 4,275,149 and 4,318,980. In some embodiments of any of the methods, a plasmablast biomarker is detected by immunohistochemistry using a diagnostic antibody (ie, a primary antibody). In some embodiments, the tissue to be analyzed is kidney tissue. In some embodiments, the diagnostic antibody specifically binds IgJ, Mzb1, or Txndc5. In some embodiments of any of the diagnostic antibodies, the diagnostic antibody is a non-human antibody. In some embodiments, the diagnostic antibody is a rat, mouse, or rabbit antibody. In some embodiments, the diagnostic antibody is a monoclonal antibody. In some embodiments, the diagnostic antibody is directly labeled. In an alternative method, a sample can be contacted with an antibody specific for that biomarker under conditions sufficient to form an antibody biomarker complex, and the complex can then be detected. The presence of biomarkers can be detected in a variety of ways, such as by Western blotting and ELISA procedures for analyzing a wide variety of tissues and samples, including plasma or serum. A wide range of immunoassay techniques using this type of analysis are available, see, for example, U.S. Patent Nos. 4,016,043, 4,424,279, and 4,018,653. These analyses include non-competitive single-point and two-point or "sandwich" analysis, as well as traditional competitive combined analysis. These analyses also include direct binding of labeled antibodies to target biomarkers. Functional or activity-type analysis can also be used to detect the presence and / or expression content / amount of selected biomarkers in a tissue or cell sample. For example, if the biomarker is an enzyme, we can perform an analysis known in the art to determine or detect the presence of a given enzyme activity in a tissue or cell sample. In certain embodiments, the sample is normalized for both the difference in the amount of biomarker analyzed and the variability in the mass of the sample used and the variability between the analyses run. This standardization can be achieved by detecting and incorporating the performance of certain standardized biomarkers, including well-known housekeeping genes such as ACTB. Alternatively, normalization may be based on the average or intermediate signals of all analyzed genes or a larger subset of them (a fully normalized approach). On a gene-by-gene basis, the measured normalized amount of mRNA or protein in an individual sample is compared with the amount found in the reference set. The normalized expression content for each mRNA or protein / test sample / subject can be expressed as a percentage of the expression content measured in the reference set. The presence and / or performance content / amount measured in a particular subject sample to be analyzed will be reduced by a few percentage points within this range, which can be determined by methods well known in the art. In some embodiments, the relative expression content of a gene is determined as follows: relative expression gene 1 sample 1 = 2 exp (Ct housekeeper gene-Ct gene 1) and Ct measured in the sample. Relative expression gene 1 reference RNA = 2 exp (Ct housekeeping gene-Ct gene 1) and Ct measured in the reference sample. Normalized relative expression gene 1 sample 1 = (relative expression gene 1 sample 1 / relative expression gene 1 reference RNA) × 100 Ct is a threshold cycle. Ct is the number of cycles, where the fluorescence generated in the reaction exceeds the threshold line. All experiments were standardized as reference RNA, which is a comprehensive mix of RNA from various tissue sources (eg, reference RNA # 636538 from Clontech, Mountain View, CA). The same reference RNA is included in each qRT-PCR run, allowing comparison of results between different experimental runs. In one embodiment, the sample is a clinical sample. In another embodiment, the sample is used for diagnostic analysis. In some embodiments, the sample is obtained from a tissue. Tissue biopsies are often used to obtain representative tissue fragments. Alternatively, tumor cells can be obtained indirectly in the form of tissues or fluids which are known or considered to contain the cells of interest. Genes or gene products can be detected from tissues or from other body samples such as urine, sputum, serum or plasma. By screening these body samples, it is easier to monitor the progress of the therapy by testing these body samples for the target gene or gene product. In certain embodiments, the reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is a single sample or multiple samples from the same subject or individual combination, in addition to obtaining one of the test samples The multiple samples are obtained at multiple different time points. For example, a reference sample, a reference cell, a reference tissue, a control sample, a control cell, or a control tissue is obtained from the same subject or individual at an earlier point in time than the test sample is obtained. This reference sample, reference cell, reference tissue, control sample, control cell, or control tissue may be useful if a reference sample is obtained during the initial diagnosis of the disease and a test sample is subsequently obtained as the disease progresses. In certain embodiments, the reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is a merged plurality of samples from one or more healthy individuals who are not the subject or individual. In certain embodiments, the reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is a combined number of individuals from one or more individuals with a disease or disorder that is not the subject or individual. Samples. In certain embodiments, the reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is a pooled RNA sample from normal tissue that is not a subject or individual or one or more individuals After pooling plasma or serum samples. In certain embodiments, the reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is from a pooled RNA sample from a tissue that is not a subject or individual or from one with a disease or disorder Pooled plasma or serum samples from one or more individuals. In certain embodiments, the reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is a sample cell line. In certain embodiments, the reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is blood. In some embodiments, the sample is a tissue sample from an individual. In some embodiments, the tissue sample is a blood or urine sample. In some embodiments, the tissue sample is a blood sample. In some embodiments of any of the methods, the BTK inhibitor is a small molecule BTK inhibitor. In some embodiments, the small molecule BTK inhibitor is Compound (A) or a pharmaceutically acceptable salt thereof. In some embodiments of any of the methods, the individual or patient according to any of the above embodiments may be a human. In another embodiment, provided herein are methods of treating SLE. In one embodiment, the method comprises administering to a subject having SLE an effective amount of a small molecule BTK inhibitor. In one such embodiment, the method further comprises administering to the individual an effective amount of at least one additional therapeutic agent, as described below. In some embodiments, the individual may be a human. The BTK inhibitors described herein can be used alone or in combination with other agents in therapy. For example, the additional therapeutic agent may be an anti-inflammatory agent, an immunomodulator, a chemotherapeutic agent, an apoptosis enhancer, a neurotrophic factor, an agent for treating cardiovascular diseases, an agent for treating liver diseases, an antiviral agent, or an agent for treating blood disorders. 5. Medicines for treating diabetes and medicines for immunodeficiency disorders. The second therapeutic agent may be an NSAID anti-inflammatory agent. The second therapeutic agent may be a chemotherapeutic agent. The second compound of the pharmaceutical combination formulation or dosing regimen preferably has the complementary activity of compound (I) so that they do not adversely affect each other. In some embodiments, the additional therapeutic agent is selected from the group consisting of a corticosteroid (eg, prednisone, prednisolone, methylprednisolone, and hydrocortisone); Disease-modifying antirheumatic drugs ("DMARD", such as immunosuppressive or anti-inflammatory agents); antimalarials (such as hydroxychloroquine and chloroquine); immunosuppressants (such as cyclophosphamide, azathioprine, mycophenol Mycophenolate mofetil, methotrexate); anti-inflammatory agents (e.g., aspirin, NSAID (e.g., ibuprofen, naproxen, indole) Indomethacin, nabumetone, celecoxib); antihypertensive agents (e.g., calcium channel blockers (e.g., amlodipine, nifedipine (e.g. nifedipine)) and diuretics (for example, furosemide)); statins (for example, atorvastatin, fluvastatin, lovastatin, lovastatin, pill Pitavastatin, pravastatin, rosuvastat in) and simvastatin); anti-B cell agents (e.g., anti-CD20 (e.g., rituximab), anti-CD22); anti-B lymphocytic stimulants ("anti-BLyS", e.g., belizumab) (belimumab, blisibimod)); type 1 interferon receptor antagonists (e.g., anifrolumab); T cell modulators (e.g., rigerimod); Abatacept; anticoagulants (eg, heparin, warfarin); and vitamin D supplements. Combination therapies can be administered simultaneously or in a sequential regimen. When administered sequentially, the combination can be administered in two or more administration forms. Combination administration includes co-administration using separate formulations or a single pharmaceutical formulation, and continuous administration in any order, with two (or all) active agents preferably exhibiting their biological activity simultaneously over a period of time. A suitable dose of any of the above co-administered medicaments is the currently used dose and can be reduced due to the combined effect (synergy) of the additional therapeutic agent. Combination therapies can be compounded such that the effects obtained when the active ingredients are used together are greater than the sum of the effects produced by the compounds used alone. Synergistic effects can be obtained when the active ingredients are: (1) simultaneously administered or delivered; (2) alternately or simultaneously administered; or (3) by some other protocol. When delivered in alternating therapies, synergistic effects can be obtained when the compound is continuously administered or delivered. In general, an effective dose of each active ingredient is administered sequentially (i.e., continuously) during alternation therapy, whereas in combination therapy, an effective dose of two or more active ingredients is administered together. In combination therapy, the kit may include (a) a first container having the dosage form composition of the present invention and, as appropriate, (b) a second pharmaceutical formulation contained therein for use with the dosage form composition of the present invention. Co-administered second container. In such aspects, the kit may include a container for containing a separate composition, such as a split bottle or a split foil pack, however, the separate composition may also be contained in a single non-separated container. Generally, the kit contains instructions for administering the individual components. The kit form is particularly useful when the individual components are preferably administered in different dosage forms (e.g., orally and parenterally), when administered at different dosing intervals, or when the prescriber needs to titrate the individual components of the combination. advantageous. BTK inhibitors can be administered by any suitable means, including oral, parenteral, intrapulmonary, and intranasal, and intralesional administration for local treatment as needed. In a preferred embodiment, a BTK inhibitor is administered orally. Oral dosage forms comprising a BTK inhibitor include, but are not limited to, lozenges or capsules comprising a BTK inhibitor or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. In some embodiments, lozenges or capsules comprising a BTK inhibitor can be administered once or twice daily according to the methods provided herein. In certain embodiments provided herein, the oral dosage form is a lozenge comprising Compound (A) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration. Depending on the short-term or long-term nature of the administration, it may be administered by any suitable route (e.g., by injection, such as intravenous or subcutaneous). Various dosing schedules are covered herein, including (but not limited to) a single administration or multiple administrations at different time points, rapid administration, and pulsed infusions. The BTK inhibitors described herein can be formulated, administered, and administered in a manner consistent with good medical practice. In this context, considerations include the specific disease or condition being treated, the specific mammal being treated, the clinical condition of the individual patient, the cause of the disease or condition, the site of delivery of the agent, the method of administration, and the timing of administration And other factors known to medical practitioners. BTK inhibitors need not be, but are optionally formulated with one or more agents currently used to prevent or treat a disease or disorder. The effective amount of these other agents depends on the amount of BTK inhibitor present in the formulation, the type of disease or disorder or treatment, and other factors as discussed above. These agents are typically used at the same dose and in the route of administration as described herein, or at about 1% to 99% of the dose described herein, or at any dose and empirically / clinically determined as appropriate Any way to use. III. contain BTK Inhibitor Therapeutic composition The compositions, methods, and kits herein provide small molecule BTK inhibitors. The small molecule BTK inhibitors provided herein are preferably organic molecules other than binding polypeptides or antibodies, and can be identified and chemically synthesized using known methods. Binding organic small molecules are typically smaller than about 2000 Daltons, and alternatively smaller than about 1500, 750, 500, 250, or 200 Daltons, where it is possible to bind (preferably, specifically) a BTK as described herein. These small organic molecules can be identified using well-known techniques without undue experimentation. In this regard, it should be noted that techniques for screening small organic libraries of molecules that can be bound to polypeptide targets are well known in the art (see, for example, PCT Publication Nos. WO 2000/00823 and WO 2000 / 39585). Binding organic small molecules can be, for example, aldehydes, ketones, oximes, amidines, semi-carbamidines, hydrazines, primary amines, secondary amines, tertiary amines, N-substituted hydrazines, hydrazine, alcohols, ethers, thiols, thioether , Disulfide, carboxylic acid, ester, ammonium, urea, carbamate, carbonate, ketal, thioketal, acetal, thioacetal, aryl halide, aryl sulfonate, alkyl Halides, alkyl sulfonates, aromatic compounds, heterocyclic compounds, anilines, olefins, alkynes, glycols, amino alcohols, oxazolines, oxazolines, thiazolines, thiazolines, enamines, sulfonium Amines, epoxides, aziridines, isocyanates, sulfonyl chlorides, diazo compounds, acid chlorides or the like. In some embodiments of any of the methods, the BTK inhibitor is selected from the group consisting of: ibrutinib, acalabrutinib, spebrutinib, BIIB068 (Biogen), BMS-986195 (Bristol-Myers Squibb), BMS-986142 (Bristol-Myers Squibb), BMS-935177 (Bristol-Myers Squibb), M2951 (Merck KGaA), PRN-1008 (Principia Biopharma), HM71224 / LY3337641 (Hanmi / Lilly), ONO-4059 / GS-4059 (Gilead / Ono), AC0058 (ACEA Biosciences), AC0025 (ACEA Biosciences), ABBV-599 (AbbVie), ABBV-105 (AbbVie), PF-303 (Pfizer), BI-BTK1 (Boehringer Ingelheim), CC90008 (Celgene), AS550 (Carna Biosciences), ARQ 531 (Arqule), AEG42766 (Aegera Therapeutics), BGB-3111 (Beigene), RN486 (Simcere Pharma), HCI- 1401 (LSK BioPharma / Hustman Cancer Inst.), KBP-7536 (KBP Bioscience), RDX002 (RedX Biopharma), SNS-062 (Sunesis), TAS5315 (Taiho Pharma), TAX-020 (Takeda), WX486 / WXFL-10230486 (WuXi AppTec / Humanwell) and X-022 (X-Rx Discovery). In some embodiments, the BTK inhibitor is Compound (A) or a pharmaceutically acceptable salt thereof. The pharmaceutically acceptable salts of the BTK inhibitors provided herein can be used in the methods herein. As used herein, the term "pharmaceutically acceptable salt" is intended to include salts of active compounds prepared with relatively non-toxic acids or bases, depending on the particular substituents present on the compounds described herein. When the compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired base in the absence of a solvent or in a suitable inert solvent. Examples of salts derived from a pharmaceutically acceptable inorganic base include aluminum salts, ammonium salts, calcium salts, copper salts, iron salts, ferrous salts, lithium salts, magnesium salts, manganese salts, manganese salts, potassium salts, Sodium, zinc and similar salts. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, including substituted amines, cyclic amines, naturally occurring amines, and the like, such as arginine, betaine , Caffeine, choline, N, N'-benzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl Morpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methyl reduced glucosamine, morpholine, piperazine, Piperidine, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of these compounds with a sufficient amount of the desired acid in the absence of a solvent or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include their acid addition salts derived from inorganic acids, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrocarbonic acid, phosphoric acid, monohydrophosphoric acid, Dihydrophosphoric acid, sulfuric acid, monohydrosulfuric acid, hydroiodic acid or phosphorous acid and similar acids; and salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzene Formic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid and the like. Also included are salts of amino acids such as arginine and similar acids, and salts of organic acids such as glucuronic acid or galacturonic acid and similar acids (see, for example, Berge, SM et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present invention contain both basic and acidic functional groups that allow the compounds to be converted into base addition salts or acid addition salts. The compound neutral form can be regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of a compound differs from various salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of the present invention, in other respects, salts are equivalent to the parent form of the compound. In addition to salt forms, the present invention provides compounds in prodrug form. As used herein, the term "prodrug" refers to those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the invention. In addition, prodrugs can be converted to compounds of the invention in an ex vivo environment by chemical or biochemical methods. For example, when a current drug is placed in a transdermal patch reservoir with a suitable enzyme or chemical agent, it can be slowly converted into a compound of the invention. The prodrugs of the present invention include compounds in which the polypeptide chain of an amino acid residue or two or more (e.g., two, three, or four) amino acid residues is covalently attached to the present invention via an amidine or ester bond Free amine, hydroxyl, or carboxylic acid groups of the compound. Amino acid residues include (but are not limited to) 20 naturally occurring amino acids commonly represented by three-letter symbols, and also include phosphoselanine, threonine phosphate, tyrosine phosphate, and 4-hydroxyproline Amino acid, hydroxy lysine, chain lysine, iso-chain lysine, γ-carboxyglutamic acid, hippuric acid, octaindole-2-carboxylic acid, statine, 1, 2, 3, 4-tetrahydroisoquinoline-3-carboxylic acid, penicillamine, ornithine, 3-methylhistidine, n-valine, β-alanine, γ-aminobutyric acid, citrulline, high Cysteine, homoserine, methyl-alanine, p-benzylidenephenylalanine, phenylglycine, propargylglycine, sarcosine, methionine, and tertiary Butylglycine. Other types of prodrugs are also covered. For example, the free carboxyl group of a compound of the invention can be derived as amidamine or an alkyl ester. As another example, a compound of the present invention containing a free hydroxyl group can be converted by, for example, but not limited to, a phosphate, a hemisuccinate, a dimethylaminoacetate, or a phosphonium oxymethyloxy group. The carbonyl group is derived as a prodrug, as outlined in Fleisher, D. et al. (1996) Improved oral drug delivery: solubility limitations overcome by the use of prodrugs Advanced Drug Delivery Reviews, 19: 115. It also includes hydroxyl and amine carbamate prodrugs, like carbonate prodrugs, and also includes hydroxyl sulfonates and sulfates. It also covers hydroxy groups derived from (fluorenyl) methyl and (fluorenyl) ethyl ether, where fluorenyl may be optionally substituted with groups including, but not limited to, ether, amine, and carboxylic acid functional groups Alkyl esters, or amino esters in which the fluorenyl group is as described above. This type of prodrug is described in J. Med. Chem., (1996), 39:10. More specific examples include the replacement of a hydrogen atom of an alcohol group with a group such as (C₁ -₆ ) Alkoxymethyl, 1-((C₁ -₆ ) Alkanoyloxy) ethyl, 1-methyl-1-((C₁ -₆ ) Alkoxy) ethyl, (C₁ -₆ ) Alkoxycarbonyloxymethyl, N- (C₁ -₆ ) Alkoxycarbonylaminomethyl, succinyl, (C₁ -₆ ) Alkyl group, α-amino group (C₁ -₄ ) Alkyl, aryl, and α-aminofluorenyl or α-aminofluorenyl-α-aminofluorenyl, wherein each α-aminofluorenyl is independently selected from naturally occurring L-amino acids , P (O) (OH)₂ , -P (O) (O (C₁ -₆ )alkyl)₂ Or glycosyl (a group resulting from removal of a hydroxyl group in the hemiacetal form of a carbohydrate). For additional examples of prodrug derivatives, see, for example, a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, vol. 42, pp. 309-396, edited by K. Widder et al. (Academic Press, 1985); b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Prodrugs", edited by H. Bundgaard, pp. 113-191 ( 1991); c) H. Bundgaard, Advanced Drug Delivery Reviews, 8: 1-38 (1992); d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77: 285 (1988); and e) N. Kakeya et al., Chem. Pharm. Bull., 32: 692 (1984), each of which is specifically incorporated herein by reference. Certain compounds of the invention may exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain compounds of the invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent to the uses covered by the present invention and are intended to be within the scope of the present invention. Certain compounds of the invention have asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereomers, geometric isomers, regioisomers, and individual isomers (e.g., individual Enantiomers) are intended to be included within the scope of this invention.IV. Pharmaceutical formulations Pharmaceutical formulations of BTK inhibitors are provided in the methods and kits herein. In some embodiments of any of the methods, from about 0.1 mg / kg / day to about 100 mg / kg / day, about 0.5 mg / kg / day to about 20 mg / kg / day, based on the patient's weight, Or, a BTK inhibitor (for example, compound (A) or a pharmaceutically acceptable salt thereof) is administered at a dose of about 1 mg / kg / day to about 10 mg / kg / day. In some embodiments, Compound (A) or a pharmaceutically acceptable salt thereof is administered as a lozenge in a dose of about 10 to 800 mg. In some embodiments, Compound (A) is administered as a free base in a lozenge at a dose of about 25 to 300 mg. In some embodiments, the lozenge contains 25 to 300 mg of compound (A) as a free base and fumaric acid, wherein the weight ratio of compound (A) to fumaric acid is about 1: 5 to about 3: 1; or about 1: 2 to about 2: 1; or about 1: 1.5 to about 1.5: 1. In some embodiments, the lozenge comprises 25 to 300 mg of compound (A) as a free base and fumaric acid, and wherein the fumaric acid content is from about 5 wt% to about 50 wt%, about 5 Wt% to about 40 wt%, about 5 wt% to about 30 wt%, about 10 wt% to about 30 wt%, about 20 wt% to about 25 wt%, about 5 wt% to about 15 wt%, or about 10 % By weight to about 15% by weight. In some of the above embodiments, the tablet weight is about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1000 mg. In some embodiments, the lozenge further comprises at least one pharmaceutically acceptable excipient selected from the group consisting of a filler, a binding agent, a disintegrant, a lubricant, and a sliding agent. In some embodiments, the lozenge comprises lactose and microcrystalline cellulose. The tablet composition of the present invention may further suitably include one or more pharmaceutically acceptable excipients selected from, but not limited to, fillers (diluents), disintegrants, binders, slip agents, and lubricants. Agent. Fillers (or diluents) can be used to increase the total volume of the powdered medicine that makes up the lozenge. Disintegrants can be used to promote the disintegration of lozenges into smaller pieces when ingested, ideally individual drug particles, and thereby facilitate rapid dissolution and absorption of the drug. Binders can be used to ensure that the granules and lozenges can be formed to have the required mechanical strength and to hold the lozenges together after they have been compressed, preventing them from disintegrating into their component powders during packaging, delivery and normal operations. Slip agents can be used to improve the flowability of the powders that make up the tablets during production. Lubricants can be used to ensure that the ingot powder does not stick to the equipment used to press the tablets during manufacturing, to improve the flow of the powder during mixing and pressing, and to minimize friction and cracking when the final tablets are sprayed from the device. Fillers and binders may include dibasic calcium phosphate, microcrystalline cellulose (Avicel®), lactose or any other suitable bulking agent. Examples of suitable fillers include microcrystalline cellulose, such as Avicel PH 101, Avicel PH102, Avicel PH 200, Avicel PH 105, Avicel DG, Ceolus KG 802, Ceolus KG 1000, SMCCSO, and Vivapur 200; lactose monohydrate, such as lactose FastFlo ; Co-processed microcrystalline cellulose with other excipients, such as co-processed microcrystalline cellulose with lactose monohydrate (MicroceLac 100) and co-processed with colloidal silica (SMCCSO, Prosolv 50, and Prosolv HD 90) Microcrystalline cellulose; mixtures of isomaltulose derivatives, such as galenIQ; and other suitable fillers and combinations thereof. The filler may be in the form of an intragranular component and / or an extragranular component. In some specific aspects, the lozenge composition of the present invention comprises lactose and microcrystalline cellulose. A disintegrant may be included in the disclosed formulation to promote the separation of the particles within the pressed product from each other and to maintain the released particles from each other. The disintegrant may be present as an intragranular component and / or an extragranular component. The disintegrant may include any suitable disintegrant such as a cross-linked polymer such as cross-linked polyvinyl pyrrolidone and cross-linked sodium carboxymethyl cellulose or cross-linked sodium carboxymethyl cellulose. In some specific aspects, the disintegrant is croscarmellose sodium. The disintegrant content is suitably about 1% by weight, about 1.5% by weight, about 2% by weight, about 2.5% by weight, about 3% by weight, about 3.5% by weight, about 4% by weight, about 4.5% by weight, or about 5% by weight. Weight percent and ranges thereof, such as about 1 weight percent to about 5 weight percent or about 2 weight percent to about 4 weight percent. Slip agents may include, for example, colloidal silica, including highly dispersed silica (Aerosil®) or any other suitable slip agent, such as animal or vegetable fats or waxes. In some specific aspects, the sliding agent is fumed silica. The slip agent content is suitably about 0.1% by weight, about 0.5% by weight, about 1% by weight, about 1.5% by weight, about 2% by weight, about 2.5% by weight, or about 3% by weight, and ranges thereof, such as about 0.1% by weight To about 3% by weight, about 0.5% to about 2% by weight, and about 0.5% to about 1.5% by weight. Lubricants can be used to compact particles in pharmaceutical compositions. Lubricants may include, for example, polyethylene glycol (e.g., a molecular weight of about 1000 to about 6000), magnesium and calcium stearate, sodium stearyl fumarate, talc, or any other suitable lubricant. In some specific aspects, the lubricant is magnesium stearate and / or sodium stearyl fumarate. The lubricant may be in the form of an intragranular component and / or an extragranular component. The lubricant content is suitably about 0.5% by weight, about 1% by weight, about 1.5% by weight, about 2% by weight, about 2.5% by weight, about 3% by weight, about 3.5% by weight, about 4% by weight, and about 4.5% by weight Or about 5 wt% and ranges thereof, such as about 0.5 wt% to about 5 wt%, about 1 wt% to about 4 wt%, about 1 wt% to about 3 wt%, or about 1 wt% to about 2 wt%. A coating, such as a film coating, may be applied to the lozenges of the invention. Film coatings can be used, for example, to help lozenges be easily swallowed. Film coating can also be used to improve taste and appearance. If desired, the film coating may be an enteric coating. The film coating may include polymerizable film-forming materials such as hydroxypropyl methyl cellulose, hydroxypropyl cellulose, acrylate or methacrylate copolymers, and polyvinyl alcohol-polyethylene glycol graft copolymers such as Opadry and Kollicoat IR. In addition to the film-forming polymer, the film coating may additionally contain plasticizers, such as polyethylene glycol; surfactants, such as Tween® type; and optionally pigments, such as titanium dioxide or iron oxide. The film coating may also contain talc as an anti-adhesive agent. Film coatings typically comprise less than about 5% by weight of the dosage form. The formulations herein may also contain more than one active ingredient necessary for the particular indication being treated, preferably those active ingredients having complementary activities that do not adversely affect each other. Such active ingredients are suitably present in combination in amounts effective to achieve the intended purpose. The active ingredients can be coated in the prepared microcapsules, for example, by coacervation technology or by interfacial polymerization, such as hydroxymethyl cellulose or gelatin microcapsules and poly (methyl methacrylate) microcapsules, respectively, in a gel. Drug delivery systems (eg, liposomes, albumin microspheres, microemulsions, nanoparticle and nanocapsules) or macroemulsions. These techniques are revealed inRemington's Pharmaceutical Sciences 16th ed., Osol, A. Ed. (1980). Delayed-release preparations can be prepared. Suitable examples of extended release formulations include semi-permeable matrices of solid hydrophobic polymers containing BTK inhibitors, which matrices are in the form of shaped articles, such as films or microcapsules. Formulations for in vivo administration are generally sterile. Sterility can be easily achieved by, for example, filtration through a sterile filtration membrane.V. product In another embodiment, an article of manufacture containing materials suitable for treating, preventing, and / or diagnosing the conditions described above is provided. Articles of manufacture include containers and markings or drug instructions on or associated with the containers. Suitable containers include, for example, bottles, vials, syringes, IV solution bags, and the like. The container can be formed from a variety of materials, such as glass or plastic. A container holds a composition itself or a combination of a composition and another composition that is effective in treating, preventing and / or diagnosing a condition, and may have a sterile access port (e.g., the container may have a needle Stopper bag or vial of intravenous solution). At least one active agent in the composition is a BTK inhibitor described herein. The indicia or the pharmaceutical label indicates that the composition is used to treat the condition of choice. In addition, the article of manufacture may comprise (a) a first container and a composition contained therein, wherein the composition comprises a BTK inhibitor; and (b) a second container and a composition contained therein, wherein the composition comprises another Cytotoxic or additional therapeutic agents. In some embodiments, the article of manufacture comprises a container, a label on the container, and a composition contained within the container; wherein the composition includes one or more reactants (bound to one or more biomarkers or described herein Primary antibodies to probes and / or primers of one or more of the biomarkers (eg, B-9 Santa Cruz Biotechnology antibodies), and a label on the container indicates that the composition can be used to evaluate one or more biomarkers in a sample Presence, and instructions for using a reagent for assessing the presence of one or more biomarkers in a sample. The article of manufacture may further include a set of instructions and materials for preparing a sample and utilizing a reagent. In some embodiments, the article of manufacture may include a reactant, such as both a primary antibody and a secondary antibody, wherein the secondary antibody is bound to a label, such as an enzyme label. In some embodiments, an article, one or more probes and / or primers directed to one or more of the biomarkers described herein. The article of manufacture in this embodiment may further include a pharmaceutical instruction sheet indicating that the composition can be used to treat a particular condition. Alternatively or in addition, the article of manufacture may further comprise a second (or third) container containing a pharmaceutically acceptable buffer such as bacteriostatic water for injection (BWFI), phosphate buffered saline, Ringer's solution (Ringer's solution) and dextrose solution. It may further include other materials required from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes. Other optional components in the preparation include one or more buffers (e.g., blocking buffer, wash buffer, substrate buffer, etc.), other reagents (such as substrates that are chemically altered by enzyme labeling) ) (Such as chromogens), epitope recovery solutions, control samples (positive and / or negative controls), control sections, and the like.Examples The following are examples of methods and compositions. It should be understood that various other embodiments may be implemented in view of the general description provided above.Blood sample analysis : 3- Analysis of Gene Plasma Cell Tag Performance. Blood was collected in a PAXgene RNA test tube (PreAnalytiX); total RNA was extracted using a commercially available kit according to the manufacturer's instructions (Qiagen).Biomarkers: IgJ, TXNDC5, MZB1.Reference gene: TMEM55B uses the Human Genome U133 Plus 2.0 array (Affymetrix Inc., Santa Clara, CA) to evaluate the performance of candidate biomarker genes in blood samples. Microarray hybridization was performed by Asuragen Inc. (Austin, TX). The original CEL archives were summed and standardized using Robust Multi-array Averaging (RMA) and analyzed using R and Bioconductor. Alternatively, the performance of candidate biomarker genes in blood samples is quantified by Fluidigm qPCR analysis. The three gene scores were calculated based on the average of IgJ, TXNDC5, and MZB1, and standardized using the reference gene TMEM55B. This analysis generated on the Cobas 4800 platform (Roche Molecular Systems) was used to evaluate blood samples.Examples 1 : Characteristics of plasmablast transcriptome Perform transcriptional analysis of CD20loCD38 + plasmablasts, CD20 + CD27 + activated B cells, and CD20 + CD27-native B cells differentiated in vitro to identify genes with strong differentiation among B cell subsets (Figure 1A-1) . At a false discovery rate (FDR) of 0.001, 86 genes were identified, and their performance in plasmablasts was> 10-fold higher than either of activated B cells or native B cells. Further refinement of these data was performed to include only genes with> 5 nRPKM in plasmablasts, resulting in a total of 40 genes. Many of these genes include heavy and light chain segments, as well as genes involved in the biosynthesis of immunoglobulin proteins. Biomarker candidates that were not part of the immunoglobulin locus were selected, so these candidates were removed from the candidate gene list (Figure 1B). It has been demonstrated that plasmablast differentiation is regulated by Bruton's tyrosine kinase (BTK) activity by performing an in vitro plasmablast differentiation assay, in which human memory B cells are placed under differentiation conditions and subsequently flow cytometry is used Cytometry quantifies CD20loCD38 ++ plasmablasts after 5 days. A specific and potent inhibitor of BTK kinase activity (GDC-0852) was used in a dose-dependent manner to inhibit CD40L-induced plasmablast differentiation (Figure 7). GDC-0852 is (S) -2- (5-fluoro-2- (hydroxymethyl) -3- (1-methyl-5- (5- (2-methyl-4- (oxetan) -3-yl) piperazin-1-yl) pyridin-2-ylamino) -6- pendantoxy-1,6-dihydropyridin-3-yl) -phenyl) -3,4,6, 7,8,9 hexahydropyrido [3,4-b] indolinazin-1 (2H) -one, the structure of which is shown below:. In order to ensure that the selected biomarker candidates can accurately determine the fraction of plasmablasts in samples with high sensitivity and specificity, 40,000 to 39 of plasmablasts derived in vitro from 3 donors are distinguished Each cell was subjected to a serial 2-fold dilution to 1,000,000 PBMCs derived from two separate donors. Fluidigm was used to assess the expression content of candidate plasmablast marker genes and was reported as ΔCt relative to the housekeeping gene HPRT1. Linear regression was used to model the ΔCt of candidate genes predicted by log10 plasmablast frequency, with plasmablast donors and PBMC donors as covariates. Most of our candidate genes show a strong correlation with plasmablast frequency and minimal differences between plasmablast donors. Three genes, IGJ, MZB1, and TXNDC5 performed particularly well, showing r of 0.84, 0.75, and 0.69, respectively² (Figures 2B-1, 2B-2, 2B-3, 2B-4). Take the average of the three genes as the label score to generate r² A label score of 0.79. To verify the genetic signature of differentiated plasmablasts in vivo, their performance was measured in plasmablasts sorted directly from healthy donors inoculated with influenza vaccinia from five weeks. All three candidate biomarker genes are more highly expressed in plasmablasts than both native and memory B cells (Figures 2C-1, 2C-2, 2C-3, 2C-4). Example 2: Plasmablast marker gene correlates with in vivo plasmablast frequency. Flow cytometry was used to measure the frequency of plasmablasts in whole blood in a lupus patient population from a ROSE phase II clinical trial [3]. , Which has paired RNA sequencing data. Selected Plasmablast Tag Genes Displayed IgD-CD19⁺ CD27⁺⁺ CD38⁺⁺ High correlation of plasmablast frequency (Figures 2D-1, 2D-2, 2D-3, 2D-4). IGJ, MZB1, and TXNDC5 showed the highest correlation coefficients with plasmablast content. Spearman correlation coefficients were 0.66, 0.71, and 0.71, respectively. The average of the three tag genes was taken as a tag to show a strong correlation with plasmablast frequency (Spearman ρ = 0.71). These results indicate that the relative abundance of plasmablasts can be measured in whole blood samples using the three selected gene tags. Example 3: Correlation between plasmablast labeling and enhanced disease activity in SLE Previous work has shown a strong correlation between plasmablast frequency and disease severity, such as by estrogen safety in lupus erythematosus ( SELENA)-Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score. This correlation appears to be driven by differences in patients with static and active disease. Observed from the Phase II clinical trial of EXPLORER [4] Moderate to severe extrarenal lupus erythematosus, and found that plasmablast cell label display has a lower but significant correlation with disease activity (Spearman ρ = 0.19, p = 0.03, Figure 3A). Looking more closely at the SLEDAI components driving this correlation, it was found that the three daughter scores in particular were particularly associated with high plasmablast abundance: DNA binding, low complement, and lymphocytopenia (Figure 3B-1, Figure 3B- 2. Figure 3B-3). A moderately negative correlation was found between plasmablast abundance and serum concentrations of complement components C3 and C4 in multiple lupus patient populations (Spilman ρ = -0.34, -0.38, respectively, Figure 3C). A moderate correlation was also observed between plasmablast content in these populations and the titer of anti-double-stranded DNA antibodies (Spearman ρ = 0.39, Figure 3C-1, Figure 3C-2, Figure 3C-3 ). Most patients with lupus display a transcriptional tag for interferon activity [2,5]. Plasmablast tags display a moderate correlation with interferon activity measured using three gene tags (Figures 3D-1 and 3D-2; [5]). The correlation appears to be driven by elevated plasmablast labeling in a subset of patients with high levels of interferon activity, with most of the lower interferon-labeled patients having lower plasmablast gene expression and high interferon activity Patients demonstrated a mix of lower plasmasomal gene expression and higher plasmasomal gene expression. However, plasmablast labeling is independent of interferon labeling and is related to disease severity and serological activity; using backward model selection, where the Akaike information criterion is used as a measure, plasmablasting and interferon labeling predicts serum complement content and plasmablastic cells Tag alone predicts anti-dsDNA antibody titer and SLEDAI. Whether as a combined score or for individual disease areas, no association was seen between plasmablast labeling scores and the British Isles Lupus Assessment Group (BILAG) activity index. These data support the role of plasmablasts in the activity of serological diseases driven by autoantibodies, lymphocytopenia, and hypocomplementemia. Example 4: Rituximab treatment reduces plasmablast cell label Plasmablast cells were collected from two moderate to severe lupus patient populations from a phase II clinical trial evaluating the safety and efficacy of rituximab in SLE The label value. These groups are patients with lupus nephritis (LUNAR) or extrarenal lupus (EXPLORER) [4,6]. The mixed effects model the plasmablast cell label value during the treatment course and incorporate the covariate age, race, combined medication, interferon activity, SLEDAI, consultation, treatment team and their interactions, where patients are modeled as random effects, Significant reductions in plasmablast labeling were identified in patients treated with rituximab (Figure 4A, Figure 4B). This effect was most apparent at the time point two weeks after receiving rituximab infusion, and the effect diminished over time. In the EXPLORER trial, two weeks after the fourth infusion of rituximab, a maximum reduction of 3.48 times was observed at week 28 (p = 2 × 10^-11 ). Similarly, in the LUNAR test, the lowest content of plasmablast labeling was observed at the 28-week time point, with a 3.31-fold reduction (p = 0.0011). In the EXPLORER test, patients are monitored for the presence of antibodies to mouse human chimeric antibodies (HACA). Although most patients treated with rituximab showed a decrease in plasmablast labeling, patients who continued to show anti-drug antibodies showed no reduction in plasmablast labeling after rituximab treatment (Figure 4C) . As described above, using the same linear mixed effects model, plasmablast marker gene expression was found to be 2.8 times higher in patients who continued to develop HACA (p = 0.0007). Example 5: Standard Nursing Care for Lupus Changes Plasmablast Cell Labeling Previous studies have identified associations between different immunosuppressive therapies and reduced plasmablast-associated gene expression [7]. Observing the screening samples from the EXPLORER clinical trial, compared with patients treated with azathioprine, extremely low plasmablast labeling was found in patients treated with mycophenolate or methotrexate (Figure 5A). A trend toward decreased plasmablast gene expression in patients from the LUNAR trial was observed in patients treated with mycophenolate at baseline (Figure 5B), although relatively few patients were in the MMF treatment pool. Example 6: Patient Race / Ethnicity Affects Plasmablast Tag Content Biomarker content often varies between patient populations. Data analysis showed significantly lower plasmablast labeling in both the EXPLORER and ROSE clinical trial populations compared to patients of European descent with African or American Hispanic descent. This is true when considering interferon activity, age, and disease severity (Figures 6A, 6B, 6C). Example 7: Effect of BTK inhibition on plasmablast differentiation: Plasmablast differentiation: Isolate memory B cells from a healthy donor PBMC (Miltenyi memory B cell isolation kit). For plasmablast differentiation, subsequent studies were performed on cytokines, IL-2 (20 U / ml), IL-10 (50 ng / ml), IL-15 (10 ng / ml), IL-6 (50 ng / ml) ), IFNa (10 ng / ml) in the presence of a mixture, culture 1.5 × 10 ^ 5 / ml memory B cells, and use ODN2006 (TLR-9 ligand) 5 ug / ml or CD40L (3 ug / ml) Stimulate for 5 days. Plasmablast differentiation was performed in the presence of a separate vehicle (DMSO) and various concentrations of GDC-0852, and titration was performed using a three-fold dose of inhibitor starting at 10 uM. Perform flow cytometry to enumerate (CD20^- CD38⁺⁺ ) Percent of plasmablasts and evaluation of GDC-0852 inhibition. RNA preparation: RNA was extracted from a cell-containing culture at 5 days, which was derived from cells treated with DMSO and GDC-0852 (370 nM) (n = 4). Cells were disrupted in RLT buffer using Qiashredder (Qiagen, Valencia, CA), and RNA was subsequently extracted using an RNeasy mini kit (Qiagen) including on-column DNase digestion. NanoDrop 8000 (Thermo Scientific) was used to determine the total RNA concentration and the integrity of the RNA sample. The isolated RNA was used for Fluidigm quantitative RT-PCR analysis. QT PCR: cDNA synthesis was performed on 100 ng total-RNA using the iScript cDNA Synthesis Kit (Biorad, Hercules, CA). Gene-specific preamplification (Applied Biosystems) was performed on 3 genes (IgJ, MZB1, TXNDC5, including the housekeeping gene TMEM55B). RT-PCR was performed using a BioMark 48.48 dynamic array (Fluidigm Corporation) using the manufacturer's protocol. Data were collected using BioMark Data Collection Software and CT values were obtained using BioMark RT-PCR Analysis Software (V.2.1.1, Fluidigm). Calculate the relative abundance (dCt) of HPRT1: 2log- (mean Ct gene-mean Ct HPRT1). For statistical analysis, set the value below the lower detection limit to 1 Ct below the lowest recorded value. Perform statistical analysis using <> or custom scripts written in R programming language. To identify differences in gene expression, we fit a linear mixed-effects model to the relative transcriptional abundance of log2 transformations, with treatment as a fixed effect and donor as a random effect. To compare the percentage of plasmablasts between DMSO and compound-treated samples, we used the Wilcoxon rank sum test. The IC50 value of BTK inhibition was calculated using GraphPad Prism software. Human recombinant interleukin (IL) -2 and interferon-α (IFN-α) were purchased from R & D system (Minneapolis, MN) and IL-10, IL-6 and IL-15 were purchased from Peprotech (Rocky Hill, NJ) . CpG (ODN2006) was purchased from Invivogen (San Deigo, CA) and CD40L was purchased from R & D Systems (Minneapolis, MN).result : Differentiation of B cells into plasmablasts can occur via multiple activation stimuli and involves different molecular changes. CD20 is activated by CD40 and / or Toll like TLR⁺ CD27⁺⁺ Memory B cells differentiate into CD20^- CD38⁺⁺ Plasmablast. We evaluated the effect of the BTK inhibitor GDC-0852 in the plasmablast differentiation method by using a CD40L-stimulated T cell-mediated response or a T cell-independent response using a Tuo receptor ligand CpG. GDC-0852 inhibited CD40L-induced plasmablast differentiation on day 5 in a dose-dependent manner, with an IC50 potency of 20.0 nM (+/- 0.002) (Figure 7). Gene expression analysis of cells treated with DMSO and GDC-0852 shows plasmablast cell tag gene IgJ(p = 0.011 ), MZB1 (p = 0.0023 ), TXNDC5 (p = 0.0032 ) And three plasma tags of compound plasmablasts (p = 0.0026 ) Significantly reduced, while native B cells displayed extremely low levels of tagged gene expression (p <1 × 10^-6 ) (Figure 8). Comparing gene expression values with plasmablast abundance, we found a strong correlation between the three gene tags and the percentage of plasmablasts (Spilman ρ = 0.81) (Figure 9). CpG-mediated plasmablast differentiation (n = 3) was also inhibited by GDC-0852, with an IC50 potency of 48 nM (+/- 57) (Figure 10). When introducing elements of the invention or its preferred embodiments, the articles "a, an", "the" and "said" mean that one or more of the elements are present. The terms "comprising", "including" and "having" are intended to be inclusive and mean that there may be elements other than the listed elements. Although the foregoing invention has been described in considerable detail by way of illustration and examples for purposes of clear understanding, these descriptions and examples should not be construed as limiting the scope. The disclosures of all patents and scientific literature cited herein are expressly incorporated herein by reference in their entirety. References 1. Arce E, Jackson DG, Gill MA, Bennett LB, Banchereau J, Pascual V. Increased frequency of pre-germinal center B cells and plasma cell precursors in the blood of children with systemic lupus erythematosus. J Immunol. 2001; 167: 2361-2369. Doi: 10.4049 / jimmunol.167.4.2361 2. Bennett L, Palucka a K, Arce E, Cantrell V, Borvak J, Banchereau J, et al. Interferon and granulopoiesis signatures in systemic lupus erythematosus blood. J Exp Med. 2003; 197: 711-723. Doi: 10.1084 / jem.20021553 3. Kalunian KC, Merrill JT, Maciuca R, McBride JM, Townsend MJ, Wei X, et al. A Phase II study of the efficacy and safety of rontalizumab (rhuMAb interferon-α) in patients with systemic lupus erythematosus (ROSE). Ann Rheum Dis. 2016; 75: 196-202. doi: 10.1136 / annrheumdis-2014-206090 4. Merrill JT, Neuwelt CM, Wallace DJ, Shanahan JC, Latinis KM, Oates JC, et al. Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus: The randomized, double-blind, pha se II / III systemic lupus erythematosus evaluation of rituximab trial. Arthritis Rheum. 2010; 62: 222-233. doi: 10.1002 / art.27233 5. Kennedy WP, Maciuca R, Wolslegel K, Tew W, Abbas AR, Chaivorapol C, et al. Association of the interferon signature metric with serological disease manifestations but not global activity scores in multiple cohorts of patients with SLE. Lupus Sci Med. 2015; 2: e000080. doi: 10.1136 / lupus-2014-000080 6. Rovin BH, Furie R, Latinis K, Looney RJ, Fervenza FC, Sanchez-Guerrero J, et al. Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the Lupus Nephritis Assessment with Rituximab study. Arthritis Rheum. 2012; 64: 1215- 1226. doi: 10.1002 / art.34359 7. Banchereau R, Hong S, Cantarel B, Baldwin N, Baisch J, Edens M, et al. Personalized Immunomonitoring Uncovers Molecular Networks that Stratify Lupus Patients. Cell. Elsevier Inc .; 2016; 165: 551-565. Doi: 10.1016 / j.cell.2016.03.008

The patent or application file contains at least one color drawing. After applying for and paying the necessary fees, the Patent Office will provide a copy of this patent or patent application publication with color graphics. Figure 1A-1 and Figure 1A-2. In vitro plasmablast differentiation and classification strategies. Plasmablasts were differentiated from CD20 + CD27 + memory B cells together with cytokines IL-2, IL-6, IL-10, IL-15, and IFNα under 7-day culture conditions containing CpG. Native B cells (CD20 + CD27-) and CD20 + CD27 + activated B cells classified by FACS and differentiated CD20loCD38 + plasmablasts were used for gene expression analysis. Figure IB. Heat map of genes specifically expressed by plasmablasts. Under the FDR of 0.001, genes with at least 10-fold higher expression in plasmablasts than in native B cells and activated B cells and plasma cells with a content> 5 RPKM were identified. Values represent stable-variance data, which are normalized to a mean of 0 within each gene and a standard deviation of 1. Figure 2A. Heat map of candidate plasmablast tag genes in PBMC samples to which an increased number of plasmablasts are added. Plasmablasts were incorporated into PBMC from two separate donors, as indicated in black and gray above the heat map. Values represent the ΔCt of each gene relative to HPRT1 and are normalized to mean 0 and standard deviation 1. Figure 2B-1 , 2B-2 , 2B - 3, and 2B-4. Compared with the percentage of plasmablasts present in each sample, relative to the expression content of plasmablast tag genes in HPRT1, or the average of all three genes value. Dotted and dashed lines indicate different PBMC donors, and different symbols indicate different donors of plasmablasts. Linear regression analysis is used to predict the performance of plasmablast cell tags or component genes, thereby incorporating PBMC donors and plasmablast donors into the model. All four models are highly statistically significant, with p <1 × 10-10. The predictive power of this model is reported as r2 from linear modeling. Figure 2C-1 , 2C-2 , 2C-3, and 2C-4. Relative performance of plasmablast genes to HPRT1 or all three tag genes measured in a B-cell population isolated from a healthy donor after receiving influenza vaccination one week The average. N = native B cells, M = memory B cells, PB = plasmablasts. Compared with other populations, plasmablasts have the highest marker gene performance. Stars indicate statistical significance of differences between B cell populations, using linear regression including donors as covariates; * = p <0.05, ** = p <0.01, *** = p <0.001. Figures 2D-1 , 2D-2 , 2D-3, and 2D-4. Plasmablast cell tags and component genes correlate with the frequency of plasmablast cells measured by FACS in the blood of patients with lupus. For a total of 96 samples, IgD-CD19 + CD27 ++ CD38 ++ plasmablasts were measured as the percentage of whole blood cells in 43 patients for up to 3 time points, and for our accompanying RNA sequencing data . Gene expression values are expressed as the RPKM of individual genes or the geometric mean RPKM of three gene tags. The correlation coefficient was calculated using Spearman's rank-order method. Figure 3A . Plasmablast labeling correlates with disease activity measured by SLEDAI. Values represent the average performance of plasmablast tag genes relative to HPRT1. The average SLEDAI and plasmablast performance values were obtained from samples collected before starting treatment. The correlation coefficient was determined using the Spearman ranking method. Figures 3B-1 , 3B-2, and 3B-3. Individual components of the SLEDAI composition index are correlated with increased plasmablast tag gene expression. Linear regression was used to analyze the statistical significance between patients who exhibited each of the symptoms and patients who did not exhibit symptoms; a star indicates the significance content in this test: * = p <0.05, ** = p <0.01 , *** = p <0.001. Figures 3C-1 , 3C-2, and 3C-3. Serum C3 and C4 complement levels and serum anti-dsDNA antibody titers correlate with plasmablast labeling performance. The correlation coefficient was calculated using the Spearman ranking method. Figures 3D-1 and 3D-2. The whole blood interferon labeling performance (ISM) correlates with plasmablast labeling. The correlation coefficient was calculated using the Spearman ranking method. Figure 4A . Treatment of patients with rituximab reduces plasmablast labeling content. Lines indicate average performance levels within the rituximab treatment group (dashed line) or placebo group (solid line), where error bars indicate the standard error of the mean. Black arrows indicate when the patient received an infusion of medication or placebo. The performance of plasmablast tag genes was modeled using a linear mixed-effects model, incorporating age, ethnicity / ethnicity, combined medications used, interferon activity, SLEDAI, and treatment team and time points and their interactions as fixed effects As well as patients with random effects. Red stars indicate significantly different time points in the rituximab-treated group in particular: * = p <0.05, ** = p <0.01, *** = p <0.001. Figure 4B . Treatment with mycophenolate mofetil and rituximab, respectively, reduces plasmablast labeling content. Lines indicate the mean of the placebo group (solid line) or the rituximab treatment group (dashed line), where the standard error of the mean is indicated by the error bar. Arrows indicate when the patient received an infusion of placebo or rituximab. Performance values were modeled using a linear mixed effects model, incorporating age, interferon activity, and treatment team and interrogation and their interactions, as well as patients with random effects. The star at the top of the graph indicates the time point in which patients treated with rituximab showed a significant decrease from baseline over the placebo group, while the star near the bottom of the graph indicates that there is no Time points: * = p <0.05, ** = p <0.01, *** = p <0.001. Figure 4C. Patients with detectable anti-chimeric antibodies (HACA) have higher plasmablast gene expression. Lines indicate the average performance of plasmablast marker genes in patients treated with rituximab that detect HACA (solid line) or those that have never detected HACA (dotted line). Error bars indicate Standard error of the mean. Figure 5A . Patients treated with mycophenolate morpholinate (MMF) or methotrexate (MTX) demonstrated lower plasmablast performance than patients treated with azathioprine (AZA). Screening plasmablast label values among patients undergoing different immunosuppressive regimens. Linear regression tests were used for statistical significance to compare AZA with each of the other two treatments. Stars indicate significant differences between treatments: * = p <0.05, ** = p <0.01, *** = p <0.001. Figure 5B. Patients treated with MMF at screening tend to have a lower plasmablast label than patients not treated with MMF. Linear regression was used to calculate p-values between patients with MMF and those without MMF at their screening visits. Figure 6A . In the EXPLORER clinical trial group, patients with European ancestry had lower plasmablast performance than other races. Values represent the mean expressed content of plasmablast genes relative to HPRT1. Use linear regression to compare screening questionnaire values among self-reported races / races. The star-shaped indications are significant compared to patients who have reported themselves as white / white: * = p <0.05, ** = p <0.01, *** = p <0.001. Figure 6B . LUNAR patients show no significant differences based on race / ethnicity. Using linear regression, no significant differences were observed in the race. Figure 6C . Patients with European ancestry in the ROSE clinical trial population show lower plasmablast performance. Values represent the geometric mean RPKM of plasmablast genes. Screening diagnostic values were compared among self-reported races / races using linear regression for log2 transformed average RPKM. The star-shaped indications are significant compared to patients who have reported themselves as white / white: * = p <0.05, ** = p <0.01, *** = p <0.001. Figure 7. Dose-response curve of CD40L-mediated plasmablast differentiation with BTK inhibitor GDC-0852 showing inhibition of plasmablast differentiation in a dose-dependent manner. FACS analysis was used to determine the percentage of plasmablasts in four healthy donors to calculate the IC50 value for each donor. Figures 8A , 8B , 8C and 8D. BTK inhibition reduces plasmablast gene tag. In the presence of DMSO vehicle or 370nM GDC-0852, memory B cells from 4 healthy donors were differentiated into plasmablasts using the conditions described above. The performance of plasmablast cell tag genes was measured by Fluidigm and standardized as the housekeeping gene (HPRT1). The performance values are plotted as the relative transcriptional abundance of the housekeeping gene. The plasmablast label was calculated as the geometric mean of the relative abundances of the three individual genes. FIG. Plasmablast gene expression related to the number of parent cells cytoplasm. The percentage of plasmablasts as determined by FACS analysis correlates with plasmablast labeling, as determined in Figure 8D (Spearman ρ = 0.81). White dots indicate the presence of differentiated samples in DMSO, while black dots indicate the samples treated with GDC-0852. FIG 10. BTK inhibitor GDC-0852 in a dose-dependent inhibition of plasma blasts manner CpG-mediated differentiation. FACS analysis was used to determine the percentage of plasmablasts in four healthy donors to calculate the IC50 value for each donor.

Claims (19)

Use of a BTK inhibitor in the manufacture of a medicament for the treatment of an individual suffering from an autoimmune or inflammatory disease, in which samples from the individual have been found to have an increased content of one selected from the group consisting of IgJ, Mzb1 and Txndc5 Or multiple biomarkers. A method of selecting a therapy for an individual suffering from an autoimmune or inflammatory disease, comprising determining the content of one or more biomarkers selected from the group consisting of IgJ, Mzb1 and Txndc5; and selecting based on the content of the biomarkers drug. A method of identifying whether an individual with an autoimmune or inflammatory disease is likely to exhibit benefit from a treatment comprising a BTK inhibitor, which comprises determining one or more of a sample from the individual selected from the group consisting of IgJ, Mzb1, and Txndc5 Biomarker content, where an increase in the biomarker content in the sample indicates that the individual is likely to exhibit benefit from treatment comprising the BTK inhibitor, or a decrease in the biomarker content indicates that the individual is unlikely to exhibit Benefit from treatments that include this BTK inhibitor. An assay for identifying an individual with an autoimmune or inflammatory disease as receiving a BTK inhibitor, the method comprising: (a) determining one or more organisms selected from the group consisting of IgJ, Mzb1, and Txndc5 in a sample from the individual The content of the marker; and (b) it is recommended to administer a BTK inhibitor based on the content of the biomarkers. A diagnostic kit comprising one or more reactants for determining the content of one or more biomarkers selected from the group consisting of IgJ, Mzb1 and Txndc5 in a sample from an individual suffering from an autoimmune or inflammatory disease Where the detection of elevated levels of these biomarkers means that the efficacy is improved when the individual is treated with a BTK inhibitor, and where the detection of lower or substantially undetectable levels of biomarkers means when The use of BTK inhibitors in treating individuals suffering from this autoimmune or inflammatory disease has reduced efficacy. The method of any one of claims 2 and 3, wherein the method further comprises administering to the individual an effective amount of a BTK inhibitor. If the purpose of claim 1, the method of claim 2 or 3, the analysis method of claim 4, or the set of claim 5, the method of measuring the content of biomarkers is to measure the biomarker content. Relative RNA content compared to reference content. If the use, method, analysis, or kit of claim 7, wherein measuring the RNA content includes amplification. If the use, method, analysis, or set of claim 8, the measurement of the RNA content includes quantitative PCR. If the use, method, analysis method or kit of claim 9, wherein measuring the content of the RNA includes amplifying the RNA and detecting the amplification product, the content of the RNA relative to the reference content is measured. If the purpose of claim 1, the method of claim 2 or 3, the analysis of claim 4, or the kit of claim 5, wherein the sample is a blood sample. If the use of claim 1, the method of claim 2 or 3, the analysis of claim 4, or the set of claim 5, wherein the BTK inhibitor is an antibody, binding polypeptide, small molecule and / or polymer Nucleotides. If the use, method, analysis or kit of claim 12, wherein the BTK inhibitor is a small molecule. If the use, method, analysis or set of claim 13, wherein the small molecule is compound (A): Or a pharmaceutically acceptable salt thereof. The use, method, analysis or kit of any one of claims 2 and 3, wherein the autoimmune or inflammatory disease is systemic lupus erythematosus. The use, method, analysis or kit of claim 15, wherein the autoimmune or inflammatory disease is lupus nephritis. The use, method, analysis or kit of claim 15, wherein the autoimmune or inflammatory disease is extrarenal lupus. If the use, method, analysis or kit of any one of claims 2 and 3 is selected, both of the biomarkers are selected. If the use, method, analysis or set of any one of claims 2 and 3 is selected, three of these biomarkers are selected.